Draft ERRγ, PPARβ, · Draft Looking beyond PGC-1 : Emerging regulators of exercise-induced...

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Looking beyond PGC-1α: Emerging regulators of exercise-induced skeletal muscle mitochondrial biogenesis and their

activation by dietary compounds

Journal: Applied Physiology, Nutrition, and Metabolism

Manuscript ID apnm-2019-0069.R2

Manuscript Type: Review

Date Submitted by the Author: 23-May-2019

Complete List of Authors: Islam, Hashim; Queen's University, School of Kinesiology and Health StudiesHood, David; York University, Muscle Health Research Centre, School of Kinesiology and Health ScienceGurd, Brendon; Queens University, School of Kinesiology and Health Studies

Keyword: mitochondria, Nrf2, ERRγ, PPARβ, LRP130, sulforaphane, quercetin, epicatechin

Is the invited manuscript for consideration in a Special

Issue? :Not applicable (regular submission)

https://mc06.manuscriptcentral.com/apnm-pubs

Applied Physiology, Nutrition, and Metabolism

DraftLooking beyond PGC-1: Emerging regulators of exercise-induced skeletal muscle

mitochondrial biogenesis and their activation by dietary compounds

Hashim Islam1, David A. Hood2 and Brendon J. Gurd1

1 School of Kinesiology and Health Studies, Queen’s University, Kingston, Ontario, Canada2 Muscle Health Research Centre, School of Kinesiology and Health Science, York University,

Toronto, Ontario, Canada

Corresponding Author:

Brendon J. Gurd, PhD Telephone: 613-533-6000 x79023

Fax: 613-533-6000Email: [email protected]

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Abstract

Despite its widespread acceptance as the “master regulator” of mitochondrial biogenesis

(i.e. the expansion of the mitochondrial reticulum), peroxisome proliferator-activated receptor

(PPAR) gamma coactivator-1 alpha (PGC-1) appears to be dispensable for the training-induced

augmentation of skeletal muscle mitochondrial content and respiratory function. In fact, a number

of regulatory protein have emerged as important players in skeletal muscle mitochondrial

biogenesis and many of these protein share key attributes with PGC-1. In an effort to move past

the simplistic notion of a “master regulator” of mitochondrial biogenesis, we highlight the

regulatory mechanisms by which nuclear factor erythroid 2-related factor 2 (Nrf2), estrogen-

related receptor gamma (ERRγ), PPARβ and leucine-rich pentatricopeptide repeat-containing

protein (LRP130) may contribute to the control of skeletal muscle mitochondrial biogenesis. We

also present evidence supporting/refuting the ability of sulforaphane, quercetin, and epicatechin to

promote skeletal muscle mitochondrial biogenesis and their potential to augment mitochondrial

training adaptations. Targeted activation of specific pathways by these compounds may allow for

greater mechanistic insight into the molecular pathways controlling mitochondrial biogenesis in

human skeletal muscle. Dietary activation of mitochondrial biogenesis may also be useful in

clinical populations with basal reductions in mitochondrial protein content, enzyme activities,

and/or respiratory function as well as individuals who exhibit a blunted skeletal muscle

responsiveness to contractile activity.

Key points:

The existence of redundant pathways leading to mitochondrial biogenesis refutes the

simplistic notion of a “master regulator” of mitochondrial biogenesis.

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Dietary activation of specific pathways may provide greater mechanistic insight into

the exercise-induced mitochondrial biogenesis in human skeletal muscle.

Keywords: mitochondria, Nrf2, ERRγ, PPARβ, LRP130, sulforaphane, quercetin, epicatechin

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Introduction

Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 alpha (PGC-1)

has gained widespread acceptance as the “master regulator” of skeletal muscle mitochondrial

biogenesis (Olesen et al. 2010; Fernandez-Marcos and Auwerx 2011; Scarpulla 2011). Although

several knockout and overexpression studies have revealed the importance of PGC-1 for the

maintenance of basal mitochondrial content, enzyme activities, and/or respiratory function (Lin et

al. 2005; Olesen et al. 2010; Scarpulla 2011), PGC-1 appears to be dispensable for training-

induced mitochondrial adaptations in rodent skeletal muscle (Hood et al. 2016). PGC-1’s non-

obligatory role in training-induced mitochondrial remodelling is perhaps unsurprising given the

complex nature of mitochondrial biogenesis, which involves the upregulated expression of two

genomes, and the subsequent synthesis, import, and assembly of newly formed proteins into the

mitochondrial reticulum (Hood et al. 2016). Therefore, the notion that a number of overlapping

and redundant pathways exist seems much more logical than the concept of a single “master

regulator” (Islam et al. 2018), particularly when considering the inherent redundancies in adaptive

pathways that defend homeostasis.

In an effort to move past the simplistic notion of a “master regulator” of mitochondrial

biogenesis and to provide avenues for future research, this review highlights several alternative

regulators of exercise-induced mitochondrial biogenesis. We also discuss a number of dietary

compounds that are believed to target some of these regulators and have the potential to augment

mitochondrial adaptations to exercise training. The latter discussion may be useful for studies

involving human skeletal muscle where targeted activation of a specific pathway could provide

greater mechanistic insight into the molecular regulation of mitochondrial biogenesis. Dietary

compounds that augment mitochondrial adaptations to training may also be of interest in clinical

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populations with basal mitochondrial defects (i.e. impairments in basal mitochondrial protein

content, morphology, enzyme activities, and/or respiratory function) and/or individuals who

exhibit blunted adaptive responses to exercise.

In the absence of a universally accepted definition, we have adopted the definition of

mitochondrial biogenesis proposed by Granata and coworkers (Granata et al. 2018) (i.e. “the

making of new components of the mitochondrial reticulum”) for the purpose of this paper. Thus,

transcriptional and post-transcriptional mechanisms that contribute to the expansion of the

mitochondrial reticulum (as reflected by an increase in mitochondrial protein content, volume

density, enzymatic activities, and/or mtDNA copy number) are presented to support/refute the

ability of a regulatory protein or dietary compound to promote mitochondrial biogenesis.

Emerging regulators of exercise-induced skeletal muscle mitochondrial biogenesis

Previously explored regulatory protein

Although we will highlight several emerging regulators of mitochondrial biogenesis in the

review below, the list of protein examined here is not comprehensive and many other regulatory

proteins are undoubtedly involved. For example, it is becoming increasingly clear that the tumour

suppressor protein p53 plays a key role in skeletal muscle remodelling in both rodents and humans

and several excellent reviews have been published on p53’s role in exercise-induced mitochondrial

biogenesis (Hood et al. 2016; Smiles and Camera 2018; Granata et al. 2018). Similarly, numerous

in vitro and ex vivo experiments have implicated sirtuin 1 (SIRT1) as a key mediator of

mitochondrial biogenesis due to its ability to deacetylate and activate nuclear PGC-1 (Gurd

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2011), though in vivo support for this paradigm is limited and largely contradictory to work

conducted in cell models (Gurd et al. 2012; Philp and Schenk 2013).

Unlike PGC-1, p53 and SIRT1, there is relatively limited information regarding the

regulatory mechanisms by which nuclear factor erythroid 2-related factor 2 (NFE2L2 or Nrf2),

estrogen-related receptor gamma (ERRγ), PPARβ and leucine-rich pentatricopeptide repeat-

containing protein (LRPPRC or LRP130) contribute to the control of mitochondrial biogenesis.

As such, it is the goal of this review is to discuss these relatively underexplored regulatory protein

in an attempt to continue and expand recent discussion of the intricacies of the mitochondrial

biogenic response to exercise. We chose to focus on these specific protein based on compelling

support for their involvement in the control of mitochondrial content and/or respiratory function

in animal and cell models, but a limited amount of evidence regarding their role in exercised human

skeletal muscle. Further, as several of the protein discussed in this article share key attributes with

PGC-1 (e.g. responsiveness to exercise and ability to coordinate the expression of nuclear- and

mitochondrial-encoded genes), they represent appropriate candidates for alternative and/or

redundant pathways by which exercise promotes mitochondrial biogenesis in skeletal muscle. We

hope the following review will promote future study of the protein discussed below thereby

pushing our understanding of exercise-induced skeletal muscle mitochondrial biogenesis forward.

Nuclear factor erythroid 2-related factor 2 (Nrf2)

I. Regulation

The transcription factor Nrf2 is a known regulator of cellular redox homeostasis and its

role in a variety of cellular processes has been investigated in various rodent models and cell lines

(see (Tebay et al. 2015) for an extensive review on this topic). Mechanisms of Nrf2 activation by

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upstream signals as well as its downstream actions are summarized in Figure 1. Basally, Nrf2’s

physical interaction with the cytosolic Kelch-like ECH-associated protein (Keap1) continuously

targets Nrf2 for proteasomal degradation (Tebay et al. 2015). During periods of cellular stress,

modifications of cysteine residues on Keap1 by reactive oxygen species (ROS) and nitric oxide

(NO) disrupt Keap1’s inhibitory interaction with Nrf2 resulting in the nuclear accumulation of

Nrf2 (Tebay et al. 2015). Once in the nucleus, Nrf2 heterodimerizes with small

musculoaponeurotic fibrosarcoma (Maf) proteins on the antioxidant response elements (ARE) of

target genes (Itoh et al. 1997) to upregulate antioxidant and detoxification enzyme gene expression

(Tebay et al. 2015) as well as its own expression (Kwak et al. 2002).

Nrf2 activity can also be modified independent of Keap1 via signalling kinases that are

activated by growth factors and intracellular stressors (Bryan et al. 2013; Tebay et al. 2015). For

instance, AMP-activated protein kinase (AMPK) directly phosphorylates Nrf2 in liver cells,

thereby promoting Nrf2’s nuclear accumulation and activation of ARE-driven gene expression

(Joo et al. 2016). Additionally, inhibition of the Nrf2 inhibitor glycogen synthase kinase-3 beta

(GSK-3β) by numerous other upstream kinases (see Figure 1) promotes Nrf2 stabilization in

various cell lines (Bryan et al. 2013; Tebay et al. 2015) as well as nuclear Nrf2 import and ARE

binding in murine cardiomyocytes (Piantadosi et al. 2008). Consistent with the ability of exercise

to activate a number of pathways involved in Nrf2 regulation (e.g. AMPK, MAPK, mTOR) (Egan

and Zierath 2013), increases in Nrf2 mRNA expression (and supposedly its activity (Kwak et al.

2002)) (Ballmann et al. 2014; Li et al. 2015; Merry and Ristow 2016), protein content (Wang et

al. 2016), and Nrf2-ARE binding (Crilly et al. 2016) have been observed in murine and/or human

skeletal muscle following acute exercise.

II. Control of mitochondrial biogenesis

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At present, the most compelling evidence for the involvement of Nrf2 in the control of

mitochondrial biogenesis is the observation that Nrf2 directly interacts with the nuclear respiratory

factor-1 (NRF-1) in mouse cardiac muscle (Piantadosi et al. 2008). NRF-1 is a transcription factor

that controls the expression of many nuclear-encoded mitochondrial genes, and the expression of

the mitochondrial transcription factors A (TFAM), B1 (TFB1M) and B2 (TFB2M) (Wu et al. 1999;

Gleyzer et al. 2005; Scarpulla 2008), allowing for the coordinated expression of nuclear- and

mitochondrial-encoded genes. Initial evidence supporting NRF-1 as a direct Nrf2 target came from

the observation that ROS production in murine cardiomyocytes results in the transcriptional

activation of mitochondrial biogenesis subsequent to an increase in Nrf2 binding to the NRF-1

promotor and the nuclear accumulation of NRF-1 protein (Piantadosi et al. 2008). Further, Nrf2

silencing in murine skeletal muscle and C2C12 cells prevents exercise- and ROS/NO – induced

increases in NRF-1 and TFAM mRNA expression (Merry and Ristow 2016). Nrf2 ablation also

prevents increases in PGC-1 and NRF-1 mRNA expression in liver tissue from mice challenged

with E. coli induced sepsis (Piantadosi et al. 2011) and blunts increases in NRF-1, TFAM and

PGC-1 protein content, mtDNA copy number, and citrate synthase (CS) activity in murine lung

tissue during pneumonia (Athale et al. 2012). Together, these findings support Nrf2’s role as a

mediator of mitochondrial biogenesis in transgenic animal and cell models in response to exercise

and oxidative/inflammatory stress.

III. Evidence for involvement in exercise-induced skeletal muscle mitochondrial biogenesis

Although Nrf2 is not required for the maintenance of basal mitochondrial content and

exercise capacity, mitochondrial respiration is impaired in skeletal muscle of whole body Nrf2

knockout mice (Crilly et al. 2016). Further, training-induced increases in skeletal muscle

mitochondrial content are blunted (Crilly et al. 2016) or completely abolished (Merry and Ristow

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2016) in Nrf2 knockout animals. Paradoxically, Nrf2 protein content decreases following training

in mice suggesting that Nrf2 may be more important for initiating mitochondrial biogenesis than

the maintenance of mitochondrial content (Crilly et al. 2016). However, it is also possible that

Nrf2 activity can increase independently from changes in protein content during training in a

fashion to similar to that of SIRT1 (Gurd et al. 2010) and p53 (Beyfuss et al. 2018). Also

noteworthy is the inverse relationship between tissue oxidative capacity and Nrf2 protein content

(tibialis anterior>soleus>heart) in mice (Crilly et al. 2016), which contrasts the tissue-specific

distribution of PGC-1 (Irrcher et al. 2003) but resembles that of SIRT1 (Gurd et al. 2009). Despite

a lack of data in exercised human skeletal muscle, nuclear Nrf2 accumulation in peripheral blood

mononuclear cells occurs in an exercise-intensity dependent manner in recreationally young males

(Done et al. 2017) and is impaired in sedentary older individuals (Done et al. 2016), highlighting

the potential impact of exercise intensity, fitness level, and/or age-group on Nrf2 activation

following exercise. Thus, preliminary evidence from training studies in mice supports Nrf2’s

importance for optimal skeletal muscle adaptation to exercise training, warranting the examination

of Nrf2’s role in the regulation of mitochondrial biogenesis in exercised human skeletal muscle.

IV. Summary

Taken together, the aforementioned studies provide evidence that: 1) Nrf2 is a stress-

responsive transcription factor that activates mitochondrial biogenesis by directly targeting NRF-

1 in mouse cardiac muscle; 2) Nrf2 is activated in rat and murine skeletal muscle in response to

acute exercise in a ROS/NO dependent manner; and 3) Nrf2 is required for basal mitochondrial

respiratory function and optimal mitochondrial adaptations to training in mouse skeletal muscle.

Importantly, the concept of NRF-1 as a common downstream target for both Nrf2 and PGC-1

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supports the existence of parallel pathways that converge on key transcription factors controlling

mitochondrial biogenesis.

Estrogen-related receptor gamma (ERR)

I. Regulation

ERR, the most recently discovered isoform of the ERR nuclear receptor family, is highly

expressed in metabolically active tissues including skeletal muscle (Narkar et al. 2011; Giguère

2008) and controls the expression of genes involved in various aspects of oxidative metabolism in

the mouse heart (Dufour et al. 2007; Alaynick et al. 2007). ERR’s transcriptional activity is

largely dependent on its interactions with various co-regulators that activate or repress ERR’s

transcriptional function (Giguère 2008). For instance, PGC-1 interacts with the activating

function (AF)-2 domain of the ERR protein in various cell models and is a major coactivator of

ERR - mediated transcription (Giguère 2008). On the other hand, receptor interacting protein 140

(RIP140) binding to the AF-2 domain represses ERR’s transcriptional activity on the promoters

of certain genes (Giguère 2008), but coactivates the ERR - mediated transcription of other genes

in HeLa cells (Castet et al. 2006). Intriguingly, ERR transactivates the PGC-1 promoter in

brown adipocytes (Wang et al. 2005), raising the possibility of an autoregulatory feedforward loop

where ERR activates its own transcriptional function via enhanced PGC-1 expression (Misra et

al. 2017). In addition to co-regulation, ERR’s activity is also modulated via post-translational

modifications by several upstream kinases in liver, kidney, and breast cancer cells (Misra et al.

2017), but it is presently unclear if ERR is phosphorylated directly within the nucleus or imported

into the nucleus after phosphorylation (see Figure 2).

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ERR gene expression is highly inducible in cellular models following increases in

intracellular stress and involves the binding of cAMP response element-binding protein (CREB),

hypoxia-inducible factor 1-alpha (HIF-1), and activating transcription factor 6-alpha (ATF-6)

to the ERR promoter (Misra et al. 2017). Consistent with the ability of exercise to activate several

upstream regulators of ERR (e.g. PGC-1, CREB, HIF-1) (Egan and Zierath 2013), ERR

mRNA expression is increased in murine skeletal muscle following exercise (Rangwala et al.

2010; Fan et al. 2018).


Basal ERR gene expression parallels oxidative capacity in murine skeletal muscle

(Rangwala et al. 2010; Narkar et al. 2011) and whole-body ERR deletion in mice is postnatally

lethal due to defective oxidative phosphorylation (OXPHOS) in the heart (Alaynick et al. 2007).

Muscle-specific ERR overexpression in mice augments skeletal muscle mitochondrial protein

content, enzyme activities, and/or respiration (Rangwala et al. 2010; Badin et al. 2016) presumably

due to ERR’s ability to upregulate the expression of genes encoding mitochondrial transcription

factors, electron transport chain (ETC) proteins, and components of the mitochondrial import and

translational machineries in rodent heart and skeletal muscle (Dufour et al. 2007; Alaynick et al.

2007; Narkar et al. 2011; Fan et al. 2018). Importantly, ERR overexpression in muscle-specific

PGC-1/ knockout mice promotes mitochondrial biogenesis and significantly improves

reductions in ETC complex activities, mtDNA copy number, and mitochondrial protein content

associated with the loss of PGC-1/, likely due to a large overlap in PGC-1/ and ERR target

genes (Fan et al. 2018).


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In addition to the rescue of basal mitochondrial defects, overexpression of ERR in muscle-

specific PGC-1/ knockout mice augments training-induced increases in exercise performance,

skeletal muscle mitochondrial protein content, and OXPHOS transcript levels (Fan et al. 2018).

Although transgenic muscle-specific ERR overexpression robustly enhances basal exercise

performance in mice (Rangwala et al. 2010; Narkar et al. 2011; Fan et al. 2018), ERR

overexpression in skeletal muscle does not potentiate training adaptations in mice with normal

levels of PGC-1/ (Fan et al. 2018), raising the possibility that ERR’s role in exercise-induced

mitochondrial remodelling may become important only in the absence of other regulators of

mitochondrial biogenesis. Although intriguing, the relevance of this scenario in humans, where

PGC-1 and other regulators of mitochondrial biogenesis are present is not readily apparent but

appears to warrant further investigation.

IV. Summary

Evidence from the aforementioned rodent studies allows for the following conclusions: 1)

ERR is required for the maintenance of mitochondrial protein content, enzyme activities, and

respiration and its basal expression closely parallels skeletal muscle oxidative capacity; 2) ERR

is responsive to exercise and directly activates genes involved in multiple aspects of skeletal

muscle mitochondrial biogenesis; and 3) ERR can promote mitochondrial biogenesis in PGC-

1/ deficient muscle. Collectively, these findings highlight the functional redundancy of ERR

and PGC-1/ in skeletal muscle and implicate ERR as an additional player in the transcriptional

control of mitochondrial biogenesis.

Peroxisome proliferator-activated receptor-beta (PPAR)

I. Regulation

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The PPAR family of nuclear hormone receptors (PPAR, PPAR, and PPAR)

heterodimerize with retinoic acid receptors (RARs) and bind to PPAR response elements (PPRE)

on target genes predominantly involved in fat metabolism (Fan et al. 2013). In the absence of a

ligand (e.g. fatty acids), PPAR interaction with co-repressors (e.g. nuclear receptor corepressor 1;

cryptochrome 1/2) inhibits their transcriptional activity, whereas PPAR-ligand binding and/or

post-translational modification (Figure 3) leads to the recruitment of co-activators (e.g. PGC-1)

and the subsequent activation of target gene transcription in cultured muscle and non-muscle cells

and/or rodent skeletal muscle (Wang et al. 2003; Dressel et al. 2003; Perez-Schindler et al. 2012;

Jordan et al. 2017). Consistent with the regulation of other PPAR family members (Burns and

Vanden Heuvel 2007), experiments involving PPAR agonists in cultured human myoblasts

indicate that AMPK and MAPK signaling cascades are involved in the control of PPAR activity

(Krämer et al. 2005). In addition, stimulation of endogenous cyclic AMP production (Hansen et

al. 2001) and protein kinase A (PKA) activation (Lazennec et al. 2000) enhances basal and ligand-

dependent PPAR activation in various cell lines. Like ERR, it is not clear if the post-translational

modulation of PPAR’s activity is an exclusively nuclear event or if modifications occurring in

the cytosol induce nuclear translocation of PPARβ.

Although PPAR mRNA expression is exercise-inducible in human skeletal muscle (Watt

et al. 2004; Perry et al. 2010; Barrès et al. 2012), the upstream events that regulate PPAR gene

expression are not well-understood. Intriguingly, a model where PPAR activates its own

promoter has been proposed (Neels and Grimaldi 2014) and is consistent with the observation of

increased endogenous PPAR protein levels with ectopic PPAR expression in mouse skeletal

muscle (Koh et al. 2017). Support for the positive feedback regulation of PPAR expression

comes from recent experiments in C2C12 and embryonic kidney cells where PPAR and AMPK

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cooperatively activate the myocyte enhancer factor 2A (MEF2A), which then binds to the PPAR

promoter to increase its activity (Koh et al. 2019). Collectively, PPAR’s activity appears to be

modulated by various intracellular signaling cascades that are responsive to exercise (Egan and

Zierath 2013) and the increase PPAR mRNA expression (and presumably its activity (Koh et al.

2019)) following acute exercise supports its potential involvement in contractile-activity induced

activation of gene transcription.


In murine skeletal muscle, transgenic muscle-specific PPAR overexpression promotes a

glycolytic-to-oxidative fibre-type shift and increases markers of mitochondrial content (Luquet et

al. 2003; Wang et al. 2004; Gan et al. 2011, 2013; Koh et al. 2017), whereas PPAR

knockdown/deletion is associated with reductions in PGC-1, NRF-1, TFAM, and ETC subunits

at the mRNA and/or protein level (Schuler et al. 2006; Koh et al. 2017). The control of

mitochondrial content by PPAR appears to be mediated by its transcriptional control of PGC-1

expression in C2C12 myocytes (Schuler et al. 2006) and its post-translational control of PGC-1

stability in murine skeletal muscle (Koh et al. 2017). However, the subcellular compartment where

the PPAR - PGC-1 interaction occurs is currently unclear. PPAR also cooperates with the

transcription factor Sp1 to increase SIRT1 promoter activity in cultured human liver cells (Okazaki

et al. 2010), thereby raising the possibility that enhanced SIRT1 expression is an additional

pathway by which PPAR modulates PGC-1 activity to promote mitochondrial biogenesis.

Recent experiments involving C2C12 muscle cells have also identified PPAR as a

transcription factor targeting NRF-1, providing a direct mechanism for PPAR-mediated induction

of mitochondrial biogenesis (Koh et al. 2017). Because NRF-1 is also a transcription factor for the

upstream AMPK activator, calcium calmodulin-dependent protein kinase kinase beta (CaMKK)

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(Koh et al. 2017), this PPAR - NRF-1 pathway may help explain the increased AMPK

phosphorylation observed with muscle-specific PPAR overexpression in mice (Gan et al. 2011;

Koh et al. 2017). Experiments in cell models also indicate that PPAR controls lactate

dehydrogenase B expression by forming a transcriptional activation complex with AMPK and

MEF2A (Gan et al. 2011), both of which are established regulators of PGC-1 (Fernandez-Marcos

and Auwerx 2011) and mitochondrial biogenesis (Scarpulla 2008, 2011; Ramachandran et al.

2008). Interestingly, PPAR expression in skeletal muscle is much greater than other PPAR

isoforms and is highest in oxidative muscle groups in mice (Wang et al. 2004). Taken together,

loss- and gain-of-function studies and the abundance of PPARβ in oxidative muscle highlight the

importance of PPAR in the control of skeletal muscle mitochondrial content through multiple

PGC-1 - dependent and independent pathways.


Transgenic muscle-specific PPAR overexpression (Gan et al. 2011; Fan et al. 2017) and

synthetic ligand-dependent PPAR activation (Narkar et al. 2008) robustly enhance exercise

performance in mice (Fan et al. 2017). In various rodent and/or human models, skeletal muscle

PPAR expression increases at the mRNA and protein level in response to acute (Watt et al. 2004;

Perry et al. 2010; Barrès et al. 2012) and chronic (Luquet et al. 2003; Koh et al. 2017) exercise,

respectively. The training-induced augmentation of PPAR protein content parallels increases in

mitochondrial protein content in rats (Koh et al. 2017) and humans (Perry et al. 2010), which

supports PPAR’s potential involvement in the adaptive response to exercise training, though

causative relationships between these variables have not been established. However, given the

importance of PPAR for the maintenance of basal mitochondrial content (Schuler et al. 2006;

Koh et al. 2017), it is reasonable to speculate that higher levels of PPAR protein and/or increased

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activity of existing PPAR protein would be required to sustain the increased demands associated

with a higher mitochondrial content after training. Consistent with the notion that PPAR activates

mitochondrial biogenesis through a dual mechanism involving PGC-1 and NRF-1, partial

knockdown of PPAR in rat skeletal muscle diminishes increases in PGC-1 and NRF-1 protein

content and markers of mitochondrial biogenesis following two weeks of swimming (Koh et al.

2017). Thus, preliminary evidence in rodents and humans supports the importance of PPAR in

skeletal muscle adaptation to training and further investigation of PPAR’s role in exercise-

induced mitochondrial biogenesis is warranted.

IV. Summary

Based on the evidence presented above, it can be concluded that: 1) PPAR is required for

the maintenance of basal mitochondrial content in murine skeletal muscle and its expression

pattern parallels skeletal muscle oxidative capacity; 2) PPAR induces mitochondrial biogenesis

through a dual mechanism involving PGC-1 and NRF-1, and also interacts with AMPK and

MEF2A to control genes involved in glucose oxidation as well as its own expression; and 3)

PPAR protein content increases following training in rodents and humans and is required for

optimal mitochondrial adaptations to training in rat skeletal muscle. It is also noteworthy that

PPAR’s ability to stimulate a fast-to-slow twitch fibre-type shift is partly dependent on ERR

(Gan et al. 2013), which (as discussed in in the previous section) directly targets genes involved

in various aspects of oxidative metabolism (Narkar et al. 2011) and can promote mitochondrial

biogenesis in PGC-1/ knockout mice (Fan et al. 2018). Collectively, PPAR’s ability to

promote oxidative remodelling in skeletal muscle both independently and cooperatively with other

putative regulators of mitochondrial content highlights its potential as a viable alternative regulator

of skeletal muscle mitochondrial biogenesis.

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Leucine-rich pentatricopeptide repeat motif-containing protein (LRP130)

I. Regulation

LRP130 is implicated in the control of mitochondrial-encoded gene expression, OXPHOS,

and fat oxidation in the liver (Cooper et al. 2006; Liu et al. 2014; Cuillerier et al. 2017). In murine

liver, LRP130 is deacetylated by sirtuin 3 (SIRT3), and is required for the SIRT3-mediated

induction of mitochondrial-encoded gene expression in response to fasting (Liu et al. 2014). In

addition, LRP130 complexes with nuclear PGC-1 in murine liver (Cooper et al. 2006), and PGC-

1/ knockdown reduces LRP130 mRNA expression in brown fat cells (Cooper et al. 2008)

implicating PGC-1/ as upstream regulators of LRP130 expression. Based on the presence of

several serine and threonine residues, LRP130 activity may also depend on phosphorylation by

ATP-dependent kinases (Hou et al. 1994), though direct evidence supporting this notion does not

presently exist. Nevertheless, LRP130’s interactions with SIRT3 and PGC-1 raises the possibility

that LRP130’s activity and/or expression may be modulated by upstream signals that are sensitive

to contraction-induced changes in the intracellular milieu (Figure 4).


LRP130 is highly expressed in metabolically active tissues with a high mitochondrial

content (e.g. heart, brown adipose tissue, skeletal muscle) and its tissue-specific distribution

parallels that of PGC-1 in mice (Cooper et al. 2008). Although a predominantly inner

mitochondrial protein (Sasarman et al. 2015), in vitro experiments demonstrate that LRP130 is

also present in nuclear fractions and promotes mRNA stability via direct RNA-binding in the

nucleus (Mili and Piñol-Roma 2003) or through its interaction with the SRA stem-loop-interacting

RNA-binding protein (SLIRP) in the mitochondria of human fibroblasts (Sasarman et al. 2010)

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and HeLa cells (Chujo et al. 2012). LRP130 also appears to control mitochondrial-encoded gene

transcription in liver cells via direct interactions with mitochondrial RNA polymerase (POLRMT)

(Liu et al. 2011, 2014) but this aspect of LRP130’s function has been questioned (Harmel et al.

2013).

LRP130 deletion in transgenic animal and cell models leads to profound reductions in the

basal expression of nearly all mitochondrial-encoded genes in the liver (Cooper et al. 2006, 2008;

Liu et al. 2014; Cuillerier et al. 2017), whereas nuclear-encoded gene expression is affected to a

lesser extent (Sasarman et al. 2010; Nam et al. 2017). The assembly and activity of several

OXPHOS complexes is also severely impaired following LRP130 deletion resulting in large

reductions in mitochondrial enzyme activities and respiration rates in various tissues (e.g. heart,

liver, BAT) (Mourier et al. 2014; Nam et al. 2017; Cuillerier et al. 2017). These impairments are

consistent with the OXPHOS complex assembly/activity defects observed in human skeletal

muscle from individuals with mitochondrial disorders that are characterized by reduced steady-

state levels of LRP130 (e.g. French-Canadian Leigh Syndrome) (Sasarman et al. 2015; Oláhová et

al. 2015). Although LRP130 loss- and gain-of-function in the aforementioned studies induces

marked changes in mitochondrial gene expression, function, and morphology (e.g. cristae density,

super-complex formation) (Liu et al. 2011; Mourier et al. 2014; Cuillerier et al. 2017) indices of

mitochondrial content appear to be unaffected (Cooper et al. 2008; Liu et al. 2011; Nam et al.

2017). Thus, LRP130 appears to contribute to the maintenance of basal mitochondrial enzyme

activities, respiration, and morphology, presumably due its transcriptional and post-transcriptional

control of mitochondrial gene expression.


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To date, only two studies have investigated LRP130’s role in skeletal muscle adaptations

to exercise (Vechetti-Junior et al. 2016; Edgett et al. 2016). In rat skeletal muscle, endurance

exercise promotes a coordinated increase in LRP130 and PGC-1 protein expression following

short-term immobilization (Vechetti-Junior et al. 2016) though markers of mitochondrial content

were not assessed in this study. On the other hand, LRP130 protein expression remains unchanged

in human skeletal muscle in response to 2-6 weeks of sprint interval training (SIT) despite a

trained-induced increase in succinate dehydrogenase activity (Edgett et al. 2016). Despite the lack

of a systematic increase in LRP130 protein, training-induced changes in LRP130, SIRT3 and PGC-

1 protein are positively correlated in human skeletal muscle (Edgett et al. 2016), supporting the

possibility of an interaction between these proteins (Cooper et al. 2006; Liu et al. 2014). Although

speculative, it is possible that changes in LRP130 activity and/or subcellular localization may

occur following exercise without changes in whole-muscle LRP130 protein content or that

LRP130 may be more important for the maintenance of basal mitochondrial enzyme activities

and/or respiratory function rather than exercise-induced mitochondrial remodelling. Nevertheless,

the lack of evidence presently available makes it difficult to support or refute LRP130’s

involvement in skeletal muscle adaptations to exercise particularly in relation to markers of

mitochondrial biogenesis, highlighting the need for future work in this area.

IV. Summary

Based on the evidence presented from various transgenic animal/cell models and/or studies

involving patients with LRP130-related mitochondrial disorders, it can be concluded that: 1)

LRP130 interacts with SIRT3 and PGC-1 in the liver to control mitochondrial gene expression

and OXPHOS activity; 2) LRP130 controls mitochondrial-encoded gene expression via

transcriptional and post-transcriptional mechanisms; and 3) LRP130 is required for the

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maintenance of mitochondrial morphology, enzyme activities, and respiratory function but appears

to be less important in the control of mitochondrial content. Although compelling, significant

research is warranted to confirm these findings in healthy humans and to determine if LRP130 is

in fact an additional player in exercise-induced skeletal muscle mitochondrial biogenesis.

Dietary activators of skeletal muscle mitochondrial biogenesis

The in vitro and transgenic animal models discussed thus far have provided valuable insight

into the molecular pathways controlling mitochondrial biogenesis. However, as complete loss- or

gain- of function is not possible in humans, dietary compounds that activate specific pathways may

allow for greater mechanistic insight into exercise-induced remodelling of skeletal muscle

mitochondria. Further, as the phenotypic changes associated with the knockdown/overexpression

of a specific protein are far more pronounced than what occurs within exercised human skeletal

muscle in vivo, targeted activation of specific pathways through dietary agents may be a more

realistic approach for understanding the roles of regulatory protein involved in mitochondrial

biogenesis. Dietary agents that amplify signaling responses to acute exercise and/or augment

skeletal muscle adaptations to training without yielding undesirable off-target effects may also be

beneficial for individuals with baseline mitochondrial defects (e.g. individuals with mitochondrial

disorders or cardiometabolic disease) and/or blunted skeletal muscle responses to contractile

activity (e.g. elderly individuals). As such, the following section highlights dietary compounds

that may be useful for examining the importance of some of the regulatory protein discussed above

in human skeletal muscle and/or augmenting mitochondrial adaptations to training.

Sulforaphane

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The isothiocyanate sulforaphane is derived from cruciferous vegetables and has the

potential to activate Nrf2 via its known ability to modify cysteine residues on Keap1 (Dinkova-

Kostova et al. 2002). Consistent with the concept of a Nrf2 – NRF-1 pathway (Piantadosi et al.

2008), sulforaphane treatment upregulates NRF-1 and TFAM mRNA expression and increases

indices of mitochondrial content in vitro and ex vivo (Whitman et al. 2013; Fernandes et al. 2015;

Zhang et al. 2016; Lei et al. 2018). In rat hepatoma cells (Axelsson et al. 2017) and/or murine

skeletal muscle (Sun et al. 2015; Oh et al. 2017), the induction of mitochondrial biogenesis by

sulforaphane is accompanied by an increase in Nrf2 nuclear import and activation, and is abolished

with NRF-1 knockdown (Negrette-Guzmán et al. 2017), thereby supporting Nrf2 as a primary

transducer of sulforaphane’s effects on the mitochondria.

Although the in vivo effects of sulforaphane on mitochondrial biogenesis remain largely

unexplored, sulforaphane administration to rodents enhances exercise performance and increases

skeletal muscle AMPK phosphorylation and Nrf2 mRNA/protein expression (Malaguti et al. 2009;

Sun et al. 2015; Oh et al. 2017). However, in contrast to in vitro work, skeletal muscle PGC-1,

NRF-1, and TFAM protein content and mtDNA copy number remain unchanged in sulforaphane

treated mice (Oh et al. 2017). Presently, information regarding sulforaphane-induced skeletal

muscle remodelling is extremely limited and, to our knowledge, the impact of sulforaphane on

exercise-induced mitochondrial biogenesis in human skeletal has not been examined. However,

the apparent safety of long-term sulforaphane supplementation in humans (Shapiro et al. 2006)

and its ability to directly activate Nrf2 underscores the importance of future work examining the

impact of sulforaphane on mitochondrial remodelling in human skeletal muscle.

Quercetin

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The polyphenol quercetin is abundant in many fruits and vegetables, making it one of the

main dietary flavonoids (Boots et al. 2008). In humans, quercetin supplementation promotes small

but significant improvements in exercise capacity (Kressler et al. 2011) and the performance

benefits of quercetin appear to be more pronounced than other polyphenol supplements

(Somerville et al. 2017). In addition to its performance benefits, quercetin treatment increases

AMPK phosphorylation, PGC-1, SIRT1, NRF-1/2, TFAM mRNA expression and/or protein

content, and indices of mitochondrial content in cultured dopaminergic neuronal cells (Ay et al.

2017), hepatocytes (Rayamajhi et al. 2013), and chondrocytes (Qiu et al. 2018). Mechanistically,

the induction of mitochondrial biogenesis by quercetin appears to be dependent on Nrf2, as a single

dose of quercetin promotes Nrf2 nuclear import in mouse brain (Li et al. 2016) and increases in

oxidative gene expression with quercetin treatment are abolished with Nrf2 knockdown in murine

hepatocytes (Kim et al. 2015). However, as little is presently known about quercetin’s impact on

the other emerging regulators of mitochondrial biogenesis discussed above, it is entirely possible

that quercetin – mediated mitochondrial biogenesis also involves the activation of additional

regulatory protein.

Evidence for the ability of quercetin to augment mitochondrial biogenesis in vivo,

particularly when combined with exercise, is currently limited and inconclusive. Although

quercetin supplementation increases PGC-1 and SIRT1 mRNA expression, and mitochondrial

content in untrained rodent skeletal muscle (Davis et al. 2009; Casuso et al. 2014), training-induced

increases in these variables are blunted with quercetin supplementation versus exercise alone

(Casuso et al. 2014). In humans, 2 weeks of quercetin supplementation (1 g/day) does not alter

mitochondrial transcript levels in trained skeletal muscle (Nieman et al. 2009), but does improve

these indices along with markers of mitochondrial content in untrained individuals (Nieman et al.

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2010). Taken together, evidence from cellular and transgenic animal models supports the ability

of quercetin to induce mitochondrial biogenesis in multiple tissues, but its effects in human skeletal

muscle and in conjunction with exercise are presently unclear.

Epicatechin

Although not as extensively studied as quercetin, a growing body of literature also supports

the efficacy of epicatechin, the primary flavanol found in dark chocolate, for inducing

mitochondrial biogenesis in various tissues. Epicatechin treatment in vitro or supplementation in

vivo increases the expression of key signaling proteins (AMPK, p38 MAPK, and SIRT1),

transcription factors and co-activators (PGC-1, MEF2A, NRF-1/2, and TFAM), mitochondrial

proteins (ETC/OXPHOS, mitofilin, porin) and/or indices of mitochondrial content/morphology

(CS activity, volume density, cristate abundance) in endothelial cells (Ramirez-Sanchez et al.

2010; Moreno-Ulloa et al. 2013), adipocytes (Varela et al. 2017), myotubes (Moreno-Ulloa et al.

2018) and/or rodent tissues (e.g. heart, brain, kidney, skeletal muscle) (Nogueira et al. 2011;

Hüttemann et al. 2013; Lee et al. 2015; Moreno-Ulloa et al. 2015). Similar effects are also observed

in skeletal muscle from sedentary humans (Taub et al. 2016), type 2 diabetics, and heart failure

patients (Taub et al. 2012, 2013) administered 100 mg of epicatechin orally for 3 months.

A limited amount of evidence also points to epicatechin’s ability to augment skeletal

muscle adaptations to training (Nogueira et al. 2011; Lee et al. 2015), though this is not a universal

finding (Schwarz et al. 2018). For example, epicatechin supplemented mice subjected to an

exercise program exhibit greater increases in exercise performance, skeletal muscle TFAM and

mitochondrial protein expression, and indices of mitochondrial content compared to trained mice

in the placebo group (Nogueira et al. 2011; Lee et al. 2015). On the other hand, a recent study

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reported that training-induced increases in aerobic fitness and skeletal muscle succinate

dehydrogenase (SDH) protein content are blunted in human participants administered 200 mg

epicatechin daily during a 4-week cycling program (Schwarz et al. 2018). Therefore, while a

relatively larger body of literature supports a favorable impact of epicatechin on skeletal muscle

mitochondrial biogenesis when compared to quercetin, much of the available evidence comes from

animal and cell models. Further, the exact mechanisms by which epicatechin activates

mitochondrial biogenesis are unclear, though NO-dependent pathways have been implicated

(Ramirez-Sanchez et al. 2010; Taub et al. 2012; Moreno-Ulloa et al. 2013) raising the possibility

of Nrf2 involvement (see Figure 1).

Conclusions and future directions

Since the first in vivo observation of skeletal muscle mitochondrial biogenesis in trained

rats (Holloszy 1967), significant advancements have been made in our understanding of the

molecular pathways that underpin this adaptive response (Perry and Hawley 2018). The discovery

of the transcriptional co-activator PGC-1 (Puigserver et al. 1998) was a major breakthrough and

a significant body of research has subsequently examined its role in mitochondrial biogenesis

(Olesen et al. 2010; Fernandez-Marcos and Auwerx 2011; Islam et al. 2018). In light of recent

work, we have highlighted several additional players with potential roles in the molecular

regulation of exercise-induced mitochondrial biogenesis. Indeed, many of these regulatory

proteins share key attributes with PGC-1, including the ability to respond to stress-activated

signaling cascades activated by exercise and the ability to upregulate the expression of nuclear-

and mitochondrial-encoded genes encoding various mitochondrial proteins (Figure 5). However,

given that the majority of the currently available evidence is derived from in vitro and/or rodent

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models, the extension of these findings to in vivo models, particularly human skeletal muscle, is

an important direction for future research. Further, as much of the available evidence is based on

transcriptional responses (i.e. changes in mRNA expression), the findings presented here should

be interpreted with caution as changes in mRNA expression do not always translate to alterations

in protein content and/or muscle phenotype (Miller et al. 2016; Robinson et al. 2017). Thus, a

greater emphasis must be placed on regulatory events distal to transcriptional/post-transcriptional

processes in future studies examining the importance of a protein or dietary compound for

promoting mitochondrial biogenesis.

Based on preliminary evidence from rodent studies highlighting Nrf2’s importance for the

transcriptional activation of mitochondrial biogenesis following acute exercise and optimal

mitochondrial remodelling following training (Crilly et al. 2016; Merry and Ristow 2016), the

examination of Nrf2’s role in the regulation of mitochondrial biogenesis in exercised human

skeletal muscle is a logical next step for future work. Further, the potential impact of various

exercise parameters (e.g. intensity, mode, duration), participant fitness level, and/or age-group on

Nrf2 activation should also be explored further given the influence of these factors on Nrf2

activation in human peripheral blood mononuclear cells (Done et al. 2016, 2017).

Similar to Nrf2, mechanistic evidence supporting the involvement of ERR and PPAR in

exercise-induced mitochondrial biogenesis in human skeletal muscle is virtually non-existent and

should be examined. Importantly, the ambiguity surrounding the subcellular localization of

functional interactions involving these proteins (e.g. PPAR - mediated stabilization of PGC-1)

and their post-translational regulation should be addressed in future experiments involving cellular

and/or transgenic animal models and if possible human tissue. Finally, the preliminary work

examining the impact of SIT on LRP130 expression in human skeletal muscle (Edgett et al. 2016)

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should be extended to include other exercise protocols that elicit robust increases in mitochondrial

biogenic markers and/or additional tissue sampling time-points to discern if LRP130 is indeed

involved in the exercise-induced remodelling of human skeletal muscle mitochondria. Relatedly,

the determination of LRP130’s fibre-specific distribution pattern and subcellular localization in

relation to markers of mitochondrial content, morphology, and/or respiratory function under basal

and exercised conditions will provide additional insight into LRP130’s role in healthy human

skeletal muscle. Collectively, these avenues should help provide a more integrative view of the

molecular underpinnings of mitochondrial remodelling following exercise.

Although several dietary compounds presented here appear to have a favorable impact on

indices of mitochondrial content based on preliminary work in vitro, their efficacy remains to be

tested in vivo, particularly in human skeletal muscle. Further, the precise molecular pathways that

mediate the effects of these compounds in vivo remain largely unknown providing an important

area for future work. Elucidation of these mechanisms may also help explain some of the

discrepancies in the literature, such as quercetin effectiveness for promoting mitochondrial

biogenesis in untrained (Nieman et al. 2010) but not trained (Nieman et al. 2009) human skeletal

muscle. Similarly, epicatechin’s potential to enhance the adaptive response to training should be

explored further in humans of varying levels of fitness levels, as existing human studies have

involved sedentary (Taub et al. 2016), untrained (Schwarz et al. 2018), and/or clinical (Taub et al.

2012, 2013) populations. Importantly, the apparent safety of these compounds for oral

administration in humans provides an excellent opportunity to further explore their acute and

chronic effects on skeletal muscle remodelling in vivo. Indeed, there are many previous examples

of compounds that induce beneficial effects in vitro yet offer little to no benefits when applied to

a human model. Perhaps one of the best-known examples of this is resveratrol, a purported SIRT1

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activator that potently induces mitochondrial biogenesis in animal/cell models, (Hood et al. 2016),

but fails to enhance (and may even impair) training adaptations in human skeletal muscle

(Williams et al. 2014; Olesen et al. 2014; Scribbans et al. 2014). Thus, verification of the evidence

presented from in vitro and rodent models in human studies is critical to determine the utility of

these dietary compounds and their potential to advance our current understanding of the molecular

regulation of mitochondrial biogenesis in skeletal muscle.

Conflict of interest

None.

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References

Alaynick, W.A., Kondo, R.P., Xie, W., He, W., Dufour, C.R., Downes, M., J., et al. 2007. ERRγ

Directs and Maintains the Transition to Oxidative Metabolism in the Postnatal Heart. Cell

Metab. 6(1): 13–24. doi:10.1016/j.cmet.2007.06.007.

Athale, J., Ulrich, A., Chou MacGarvey, N., Bartz, R.R., Welty-Wolf, K.E., Suliman, H.B., and

Piantadosi, C.A. 2012. Nrf2 promotes alveolar mitochondrial biogenesis and resolution of

lung injury in Staphylococcus aureus pneumonia in mice. Free Radic. Biol. Med. 53(8):

1584–1594. doi:10.1016/j.freeradbiomed.2012.08.009.

Axelsson, A.S., Tubbs, E., Mecham, B., Chacko, S., Nenonen, H.A., Tang, Y., et al. 2017.

Sulforaphane reduces hepatic glucose production and improves glucose control in patients

with type 2 diabetes. Sci. Transl. Med. 9(394): eaah4477.

doi:10.1126/scitranslmed.aah4477.

Ay, M., Luo, J., Langley, M., Jin, H., Anantharam, V., Kanthasamy, A., and Kanthasamy, A.G.

2017. Molecular mechanisms underlying protective effects of quercetin against

mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture

and MitoPark transgenic mouse models of Parkinson’s Disease. J. Neurochem. 141(5):

766–782. doi:10.1111/jnc.14033.

Badin, P.-M., Vila, I.K., Sopariwala, D.H., Yadav, V., Lorca, S., Louche, K., et al. 2016. Exercise-

like effects by Estrogen-related receptor-gamma in muscle do not prevent insulin resistance

in db/db mice. Sci. Rep. 6(1). doi:10.1038/srep26442.

Ballmann, C., McGinnis, G., Peters, B., Slivka, D., Cuddy, J., Hailes, W., et al. 2014. Exercise-

induced oxidative stress and hypoxic exercise recovery. Eur. J. Appl. Physiol. 114(4): 725–

733. doi:10.1007/s00421-013-2806-5.

Page 28 of 55



Draft

29

Barrès, R., Yan, J., Egan, B., Treebak, J.T., Rasmussen, M., Fritz, T., et al. 2012. Acute Exercise

Remodels Promoter Methylation in Human Skeletal Muscle. Cell Metab. 15(3): 405–411.

doi:10.1016/j.cmet.2012.01.001.

Beyfuss, K., Erlich, A.T., Triolo, M., and Hood, D.A. 2018. The Role of p53 in Determining

Mitochondrial Adaptations to Endurance Training in Skeletal Muscle. Sci. Rep. 8(1).

doi:10.1038/s41598-018-32887-0.

Boots, A.W., Haenen, G.R.M.M., and Bast, A. 2008. Health effects of quercetin: from antioxidant

to nutraceutical. Eur. J. Pharmacol. 585(2–3): 325–337. doi:10.1016/j.ejphar.2008.03.008.

Bryan, H.K., Olayanju, A., Goldring, C.E., and Park, B.K. 2013. The Nrf2 cell defence pathway:

Keap1-dependent and -independent mechanisms of regulation. Biochem. Pharmacol.

85(6): 705–717. doi:10.1016/j.bcp.2012.11.016.

Burns, K.A., and Vanden Heuvel, J.P. 2007. Modulation of PPAR activity via phosphorylation.

Biochim. Biophys. Acta 1771(8): 952–960. doi:10.1016/j.bbalip.2007.04.018.

Castet, A., Herledan, A., Bonnet, S., Jalaguier, S., Vanacker, J.-M., and Cavaillès, V. 2006.

Receptor-Interacting Protein 140 Differentially Regulates Estrogen Receptor-Related

Receptor Transactivation Depending on Target Genes. Mol. Endocrinol. 20(5): 1035–

1047. doi:10.1210/me.2005-0227.

Casuso, R.A., Martínez-López, E.J., Nordsborg, N.B., Hita-Contreras, F., Martínez-Romero, R.,

Cañuelo, A., and Martínez-Amat, A. 2014. Oral quercetin supplementation hampers

skeletal muscle adaptations in response to exercise training: Quercetin, exercise, muscle

plasticity. Scand. J. Med. Sci. Sports 24(6): 920–927. doi:10.1111/sms.12136.

Chujo, T., Ohira, T., Sakaguchi, Y., Goshima, N., Nomura, N., Nagao, A., and Suzuki, T. 2012.

LRPPRC/SLIRP suppresses PNPase-mediated mRNA decay and promotes

Page 29 of 55



Draft

30

polyadenylation in human mitochondria. Nucleic Acids Res. 40(16): 8033–8047.

doi:10.1093/nar/gks506.

Cooper, M.P., Qu, L., Rohas, L.M., Lin, J., Yang, W., Erdjument-Bromage, H., et al. 2006. Defects

in energy homeostasis in Leigh syndrome French Canadian variant through PGC-1

/LRP130 complex. Genes Dev. 20(21): 2996–3009. doi:10.1101/gad.1483906.

Cooper, M.P., Uldry, M., Kajimura, S., Arany, Z., and Spiegelman, B.M. 2008. Modulation of

PGC-1 Coactivator Pathways in Brown Fat Differentiation through LRP130. J. Biol.

Chem. 283(46): 31960–31967. doi:10.1074/jbc.M805431200.

Crilly, M.J., Tryon, L.D., Erlich, A.T., and Hood, D.A. 2016. The role of Nrf2 in skeletal muscle

contractile and mitochondrial function. J. Appl. Physiol. 121(3): 730–740.

doi:10.1152/japplphysiol.00042.2016.

Cuillerier, A., Honarmand, S., Cadete, V.J.J., Ruiz, M., Forest, A., Deschênes, S., Beauchamp, C.,

et al. 2017. Loss of hepatic LRPPRC alters mitochondrial bioenergetics, regulation of

permeability transition and trans-membrane ROS diffusion. Hum. Mol. Genet. 26(16):

3186–3201. doi:10.1093/hmg/ddx202.

Davis, J.M., Murphy, E.A., Carmichael, M.D., and Davis, B. 2009. Quercetin increases brain and

muscle mitochondrial biogenesis and exercise tolerance. Am. J. Physiol.-Regul. Integr.

Comp. Physiol. 296(4): R1071–R1077. doi:10.1152/ajpregu.90925.2008.

Dinkova-Kostova, A.T., Holtzclaw, W.D., Cole, R.N., Itoh, K., Wakabayashi, N., Katoh, Y., et al.

2002. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction

of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl. Acad. Sci.

U. S. A. 99(18): 11908–11913. doi:10.1073/pnas.172398899.

Page 30 of 55



Draft

31

Done, A.J., Gage, M.J., Nieto, N.C., and Traustadóttir, T. 2016. Exercise-induced Nrf2-signaling

is impaired in aging. Free Radic. Biol. Med. 96: 130–138.

doi:10.1016/j.freeradbiomed.2016.04.024.

Done, A.J., Newell, M.J., and Traustadóttir, T. 2017. Effect of exercise intensity on Nrf2 signalling

in young men. Free Radic. Res. 51(6): 646–655. doi:10.1080/10715762.2017.1353689.

Dressel, U., Allen, T.L., Pippal, J.B., Rohde, P.R., Lau, P., and Muscat, G.E.O. 2003. The

Peroxisome Proliferator-Activated Receptor β/δ Agonist, GW501516, Regulates the

Expression of Genes Involved in Lipid Catabolism and Energy Uncoupling in Skeletal

Muscle Cells. Mol. Endocrinol. 17(12): 2477–2493. doi:10.1210/me.2003-0151.

Dufour, C.R., Wilson, B.J., Huss, J.M., Kelly, D.P., Alaynick, W.A., Downes, M., et al. 2007.

Genome-wide Orchestration of Cardiac Functions by the Orphan Nuclear Receptors ERRα

and γ. Cell Metab. 5(5): 345–356. doi:10.1016/j.cmet.2007.03.007.

Edgett, B.A., Bonafiglia, J.T., Baechler, B.L., Quadrilatero, J., and Gurd, B.J. 2016. The effect of

acute and chronic sprint-interval training on LRP130, SIRT3, and PGC-1 α expression in

human skeletal muscle. Physiol. Rep. 4(17): e12879. doi:10.14814/phy2.12879.

Egan, B., and Zierath, J.R. 2013. Exercise Metabolism and the Molecular Regulation of Skeletal

Muscle Adaptation. Cell Metab. 17(2): 162–184. doi:10.1016/j.cmet.2012.12.012.

Fan, W., Atkins, A.R., Yu, R.T., Downes, M., and Evans, R.M. 2013. Road to exercise mimetics:

targeting nuclear receptors in skeletal muscle. J. Mol. Endocrinol. 51(3): T87–T100.

doi:10.1530/JME-13-0258.

Fan, W., He, N., Lin, C.S., Wei, Z., Hah, N., Waizenegger, W., et al. 2018. ERRγ Promotes

Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1α/β-

Deficient Muscle. Cell Rep. 22(10): 2521–2529. doi:10.1016/j.celrep.2018.02.047.

Page 31 of 55



Draft

32

Fan, W., Waizenegger, W., Lin, C.S., Sorrentino, V., He, M.-X., Wall, C.E., et al. 2017. PPARδ

Promotes Running Endurance by Preserving Glucose. Cell Metab. 25(5): 1186-1193.e4.

doi:10.1016/j.cmet.2017.04.006.

Fernandes, R.O., Bonetto, J.H.P., Baregzay, B., de Castro, A.L., Puukila, S., Forsyth, H., et al.

2015. Modulation of apoptosis by sulforaphane is associated with PGC-1α stimulation and

decreased oxidative stress in cardiac myoblasts. Mol. Cell. Biochem. 401(1–2): 61–70.

doi:10.1007/s11010-014-2292-z.

Fernandez-Marcos, P.J., and Auwerx, J. 2011. Regulation of PGC-1α, a nodal regulator of

mitochondrial biogenesis. Am. J. Clin. Nutr. 93(4): 884S-890S.

doi:10.3945/ajcn.110.001917.

Gan, Z., Burkart-Hartman, E.M., Han, D.-H., Finck, B., Leone, T.C., Smith, E.Y., et al. 2011. The

nuclear receptor PPAR / programs muscle glucose metabolism in cooperation with AMPK

and MEF2. Genes Dev. 25(24): 2619–2630. doi:10.1101/gad.178434.111.

Gan, Z., Rumsey, J., Hazen, B.C., Lai, L., Leone, T.C., Vega, R.B., et al. 2013. Nuclear

receptor/microRNA circuitry links muscle fiber type to energy metabolism. J. Clin. Invest.

123(6): 2564–2575. doi:10.1172/JCI67652.

Giguère, V. 2008. Transcriptional Control of Energy Homeostasis by the Estrogen-Related

Receptors. Endocr. Rev. 29(6): 677–696. doi:10.1210/er.2008-0017.

Gleyzer, N., Vercauteren, K., and Scarpulla, R.C. 2005. Control of mitochondrial transcription

specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-

2) and PGC-1 family coactivators. Mol. Cell. Biol. 25(4): 1354–1366.

doi:10.1128/MCB.25.4.1354-1366.2005.

Page 32 of 55



Draft

33

Granata, C., Jamnick, N.A., and Bishop, D.J. 2018. Principles of Exercise Prescription, and How

They Influence Exercise-Induced Changes of Transcription Factors and Other Regulators

of Mitochondrial Biogenesis. Sports Med. 48(7): 1541–1559. doi:10.1007/s40279-018-

0894-4.

Gurd, B.J. 2011. Deacetylation of PGC-1α by SIRT1: importance for skeletal muscle function and

exercise-induced mitochondrial biogenesis. Appl. Physiol. Nutr. Metab. Physiol. Appl.

Nutr. Metab. 36(5): 589–597. doi:10.1139/h11-070.

Gurd, B.J., Little, J.P., and Perry, C.G.R. 2012. Does SIRT1 determine exercise-induced skeletal

muscle mitochondrial biogenesis: differences between in vitro and in vivo experiments? J.

Appl. Physiol. 112(5): 926–928. doi:10.1152/japplphysiol.01262.2011.

Gurd, B.J., Perry, C.G.R., Heigenhauser, G.J.F., Spriet, L.L., and Bonen, A. 2010. High-intensity

interval training increases SIRT1 activity in human skeletal muscle. Appl. Physiol. Nutr.

Metab. 35(3): 350–357. doi:10.1139/H10-030.

Gurd, B.J., Yoshida, Y., Lally, J., Holloway, G.P., and Bonen, A. 2009. The deacetylase enzyme

SIRT1 is not associated with oxidative capacity in rat heart and skeletal muscle and its

overexpression reduces mitochondrial biogenesis. J. Physiol. 587(Pt 8): 1817–1828.

doi:10.1113/jphysiol.2008.168096.

Hansen, J.B., Zhang, H., Rasmussen, T.H., Petersen, R.K., Flindt, E.N., and Kristiansen, K. 2001.

Peroxisome Proliferator-activated Receptor δ (PPARδ)-mediated Regulation of

Preadipocyte Proliferation and Gene Expression Is Dependent on cAMP Signaling. J. Biol.

Chem. 276(5): 3175–3182. doi:10.1074/jbc.M005567200.

Harmel, J., Ruzzenente, B., Terzioglu, M., Spåhr, H., Falkenberg, M., and Larsson, N.-G. 2013.

The Leucine-rich Pentatricopeptide Repeat-containing Protein (LRPPRC) Does Not

Page 33 of 55



Draft

34

Activate Transcription in Mammalian Mitochondria. J. Biol. Chem. 288(22): 15510–

15519. doi:10.1074/jbc.M113.471649.

Holloszy, J.O. 1967. Biochemical adaptations in muscle. Effects of exercise on mitochondrial

oxygen uptake and respiratory enzyme activity in skeletal muscle. J. Biol. Chem. 242(9):

2278–2282.

Hood, D.A., Tryon, L.D., Carter, H.N., Kim, Y., and Chen, C.C.W. 2016. Unravelling the

mechanisms regulating muscle mitochondrial biogenesis. Biochem. J. 473(15): 2295–

2314. doi:10.1042/BCJ20160009.

Hou, J., Wang, F., and McKeehan, W.L. 1994. Molecular cloning and expression of the gene for

a major leucine-rich protein from human hepatoblastoma cells (HepG2). In Vitro Cell. Dev.

Biol. Anim. 30A(2): 111–114.

Hüttemann, M., Lee, I., Perkins, G.A., Britton, S.L., Koch, L.G., and Malek, M.H. 2013. (–)-

Epicatechin is associated with increased angiogenic and mitochondrial signalling in the

hindlimb of rats selectively bred for innate low running capacity. Clin. Sci. 124(11): 663–

674. doi:10.1042/CS20120469.

Irrcher, I., Adhihetty, P.J., Sheehan, T., Joseph, A.-M., and Hood, D.A. 2003. PPARγ coactivator-

1α expression during thyroid hormone- and contractile activity-induced mitochondrial

adaptations. Am. J. Physiol.-Cell Physiol. 284(6): C1669–C1677.

doi:10.1152/ajpcell.00409.2002.

Islam, H., Edgett, B.A., and Gurd, B.J. 2018. Coordination of mitochondrial biogenesis by PGC-

1α in human skeletal muscle: A re-evaluation. Metabolism 79: 42–51.

doi:10.1016/j.metabol.2017.11.001.

Page 34 of 55



Draft

35

Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., et al. 1997. An Nrf2/Small Maf

Heterodimer Mediates the Induction of Phase II Detoxifying Enzyme Genes through

Antioxidant Response Elements. Biochem. Biophys. Res. Commun. 236(2): 313–322.

doi:10.1006/bbrc.1997.6943.

Joo, M.S., Kim, W.D., Lee, K.Y., Kim, J.H., Koo, J.H., and Kim, S.G. 2016. AMPK Facilitates

Nuclear Accumulation of Nrf2 by Phosphorylating at Serine 550. Mol. Cell. Biol. 36(14):

1931–1942. doi:10.1128/MCB.00118-16.

Jordan, S.D., Kriebs, A., Vaughan, M., Duglan, D., Fan, W., Henriksson, E., et al. 2017. CRY1/2

Selectively Repress PPARδ and Limit Exercise Capacity. Cell Metab. 26(1): 243-255.e6.

doi:10.1016/j.cmet.2017.06.002.

Kim, C.-S., Kwon, Y., Choe, S.-Y., Hong, S.-M., Yoo, H., Goto, T., et al. 2015. Quercetin reduces

obesity-induced hepatosteatosis by enhancing mitochondrial oxidative metabolism via

heme oxygenase-1. Nutr. Metab. 12(1). doi:10.1186/s12986-015-0030-5.

Koh, J.-H., Hancock, C.R., Han, D.-H., Holloszy, J.O., Nair, K.S., and Dasari, S. 2019. AMPK

and PPARβ positive feedback loop regulates endurance exercise-mediated GLUT4

expression in skeletal muscle. Am. J. Physiol.-Endocrinol. Metab.

doi:10.1152/ajpendo.00460.2018.

Koh, J.-H., Hancock, C.R., Terada, S., Higashida, K., Holloszy, J.O., and Han, D.-H. 2017. PPARβ

Is Essential for Maintaining Normal Levels of PGC-1α and Mitochondria and for the

Increase in Muscle Mitochondria Induced by Exercise. Cell Metab. 25(5): 1176-1185.e5.

doi:10.1016/j.cmet.2017.04.029.

Page 35 of 55



Draft

36

Krämer, D.K., Al-Khalili, L., Perrini, S., Skogsberg, J., Wretenberg, P., Kannisto, K., et al. 2005.

Direct activation of glucose transport in primary human myotubes after activation of

peroxisome proliferator-activated receptor delta. Diabetes 54(4): 1157–1163.

Kressler, J., Millard-Stafford, M., and Warren, G.L. 2011. Quercetin and Endurance Exercise

Capacity: A Systematic Review and Meta-analysis. Med. Sci. Sports Exerc. 43(12): 2396–

2404. doi:10.1249/MSS.0b013e31822495a7.

Kwak, M.-K., Itoh, K., Yamamoto, M., and Kensler, T.W. 2002. Enhanced expression of the

transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response

element-like sequences in the nrf2 promoter. Mol. Cell. Biol. 22(9): 2883–2892.

Lazennec, G., Canaple, L., Saugy, D., and Wahli, W. 2000. Activation of peroxisome proliferator-

activated receptors (PPARs) by their ligands and protein kinase A activators. Mol.

Endocrinol. Baltim. Md 14(12): 1962–1975. doi:10.1210/mend.14.12.0575.

Lee, I., Hüttemann, M., Kruger, A., Bollig-Fischer, A., and Malek, M.H. 2015. (–)–Epicatechin

combined with 8 weeks of treadmill exercise is associated with increased angiogenic and

mitochondrial signaling in mice. Front. Pharmacol. 6. doi:10.3389/fphar.2015.00043.

Lei, P., Tian, S., Teng, C., Huang, L., Liu, X., Wang, J., et al. 2018. Sulforaphane Improves Lipid

Metabolism by Enhancing Mitochondrial Function and Biogenesis in vivo and vitro. Mol.

Nutr. Food Res.: 1800795. doi:10.1002/mnfr.201800795.

Li, T., He, S., Liu, S., Kong, Z., Wang, J., and Zhang, Y. 2015. Effects of different exercise

durations on Keap1-Nrf2-ARE pathway activation in mouse skeletal muscle. Free Radic.

Res. 49(10): 1269–1274. doi:10.3109/10715762.2015.1066784.

Page 36 of 55



Draft

37

Li, X., Wang, H., Gao, Y., Li, L., Tang, C., Wen, G., et al. 2016. Protective Effects of Quercetin

on Mitochondrial Biogenesis in Experimental Traumatic Brain Injury via the Nrf2

Signaling Pathway. PLOS ONE 11(10): e0164237. doi:10.1371/journal.pone.0164237.

Lin, J., Handschin, C., and Spiegelman, B.M. 2005. Metabolic control through the PGC-1 family

of transcription coactivators. Cell Metab. 1(6): 361–370. doi:10.1016/j.cmet.2005.05.004.

Liu, L., Nam, M., Fan, W., Akie, T.E., Hoaglin, D.C., Gao, G., et al. 2014. Nutrient sensing by the

mitochondrial transcription machinery dictates oxidative phosphorylation. J. Clin. Invest.

124(2): 768–784. doi:10.1172/JCI69413.

Liu, L., Sanosaka, M., Lei, S., Bestwick, M.L., Frey, J.H., Surovtseva, Y.V., et al. 2011. LRP130

Protein Remodels Mitochondria and Stimulates Fatty Acid Oxidation. J. Biol. Chem.

286(48): 41253–41264. doi:10.1074/jbc.M111.276121.

Luquet, S., Lopez-Soriano, J., Holst, D., Fredenrich, A., Melki, J., Rassoulzadegan, M., and

Grimaldi, P.A. 2003. Peroxisome proliferator-activated receptor δ controls muscle

development and oxidative capability. FASEB J. 17(15): 2299–2301. doi:10.1096/fj.03-

0269fje.

Malaguti, M., Angeloni, C., Garatachea, N., Baldini, M., Leoncini, E., Collado, P.S., et al. 2009.

Sulforaphane treatment protects skeletal muscle against damage induced by exhaustive

exercise in rats. J. Appl. Physiol. Bethesda Md 1985 107(4): 1028–1036.


Merry, T.L., and Ristow, M. 2016. Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2)

mediates exercise-induced mitochondrial biogenesis and the anti-oxidant response in mice:

NFE2L2 and mitochondrial biogenesis. J. Physiol. 594(18): 5195–5207.

doi:10.1113/JP271957.

Page 37 of 55



Draft

38

Mili, S., and Piñol-Roma, S. 2003. LRP130, a pentatricopeptide motif protein with a noncanonical

RNA-binding domain, is bound in vivo to mitochondrial and nuclear RNAs. Mol. Cell.

Biol. 23(14): 4972–4982.

Miller, B.F., Konopka, A.R., and Hamilton, K.L. 2016. The rigorous study of exercise adaptations:

why mRNA might not be enough. J. Appl. Physiol. 121(2): 594–596.


Misra, J., Kim, D.-K., and Choi, H.-S. 2017. ERRγ: a Junior Orphan with a Senior Role in

Metabolism. Trends Endocrinol. Metab. TEM 28(4): 261–272.

doi:10.1016/j.tem.2016.12.005.

Moreno-Ulloa, A., Cid, A., Rubio-Gayosso, I., Ceballos, G., Villarreal, F., and Ramirez-Sanchez,

I. 2013. Effects of (−)-epicatechin and derivatives on nitric oxide mediated induction of

mitochondrial proteins. Bioorg. Med. Chem. Lett. 23(15): 4441–4446.

doi:10.1016/j.bmcl.2013.05.079.

Moreno-Ulloa, A., Miranda-Cervantes, A., Licea-Navarro, A., Mansour, C., Beltrán-Partida, E.,

Donis-Maturano, L., et al. 2018. (-)-Epicatechin stimulates mitochondrial biogenesis and

cell growth in C2C12 myotubes via the G-protein coupled estrogen receptor. Eur. J.

Pharmacol. 822: 95–107. doi:10.1016/j.ejphar.2018.01.014.

Moreno-Ulloa, A., Nogueira, L., Rodriguez, A., Barboza, J., Hogan, M.C., Ceballos, et al. 2015.

Recovery of Indicators of Mitochondrial Biogenesis, Oxidative Stress, and Aging With

(−)-Epicatechin in Senile Mice. J. Gerontol. A. Biol. Sci. Med. Sci. 70(11): 1370–1378.

doi:10.1093/gerona/glu131.

Page 38 of 55



Draft

39

Mourier, A., Ruzzenente, B., Brandt, T., Kuhlbrandt, W., and Larsson, N.-G. 2014. Loss of

LRPPRC causes ATP synthase deficiency. Hum. Mol. Genet. 23(10): 2580–2592.

doi:10.1093/hmg/ddt652.

Nam, M., Akie, T.E., Sanosaka, M., Craige, S.M., Kant, S., Jr, J.F.K., and Cooper, M.P. 2017.

Mitochondrial retrograde signaling connects respiratory capacity to thermogenic gene

expression. Sci. Rep. 7(1): 2013. doi:10.1038/s41598-017-01879-x.

Narkar, V.A., Downes, M., Yu, R.T., Embler, E., Wang, Y.-X., Banayo, E., et al. 2008. AMPK

and PPARδ Agonists Are Exercise Mimetics. Cell 134(3): 405–415.

doi:10.1016/j.cell.2008.06.051.

Narkar, V.A., Fan, W., Downes, M., Yu, R.T., Jonker, J.W., Alaynick, W.A., et al. 2011. Exercise

and PGC-1α-Independent Synchronization of Type I Muscle Metabolism and Vasculature

by ERRγ. Cell Metab. 13(3): 283–293. doi:10.1016/j.cmet.2011.01.019.

Neels, J.G., and Grimaldi, P.A. 2014. Physiological Functions of Peroxisome Proliferator-

Activated Receptor β. Physiol. Rev. 94(3): 795–858. doi:10.1152/physrev.00027.2013.

Negrette-Guzmán, M., Huerta-Yepez, S., Vega, M.I., León-Contreras, J.C., Hernández-Pando, R.,

Medina-Campos, O.N., et al. 2017. Sulforaphane induces differential modulation of

mitochondrial biogenesis and dynamics in normal cells and tumor cells. Food Chem.

Toxicol. 100: 90–102. doi:10.1016/j.fct.2016.12.020.

Nieman, D.C., Henson, D.A., Maxwell, K.R., Williams, A.S., Mcanulty, S.R., Jin, F., et al. 2009.

Effects of Quercetin and EGCG on Mitochondrial Biogenesis and Immunity: Med. Sci.

Sports Exerc. 41(7): 1467–1475. doi:10.1249/MSS.0b013e318199491f.

Page 39 of 55



Draft

40

Nieman, D.C., Williams, A.S., Shanely, R.A., Jin, F., Mcanulty, S.R., Triplett, N.T., et al. 2010.

Quercetin’s Influence on Exercise Performance and Muscle Mitochondrial Biogenesis:

Med. Sci. Sports Exerc. 42(2): 338–345. doi:10.1249/MSS.0b013e3181b18fa3.

Nogueira, L., Ramirez-Sanchez, I., Perkins, G.A., Murphy, A., Taub, P.R., Ceballos, G., et al.

2011. (-)-Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle:

(-)-Epicatechin and muscle adaptation. J. Physiol. 589(18): 4615–4631.

doi:10.1113/jphysiol.2011.209924.

Oh, S., Komine, S., Warabi, E., Akiyama, K., Ishii, A., Ishige, K., et al. 2017. Nuclear factor

(erythroid derived 2)-like 2 activation increases exercise endurance capacity via redox

modulation in skeletal muscles. Sci. Rep. 7(1). doi:10.1038/s41598-017-12926-y.

Okazaki, M., Iwasaki, Y., Nishiyama, M., Taguchi, T., Tsugita, M., Nakayama, S., et al. 2010.

PPARbeta/delta regulates the human SIRT1 gene transcription via Sp1. Endocr. J. 57(5):

403–413.

Oláhová, M., Hardy, S.A., Hall, J., Yarham, J.W., Haack, T.B., Wilson, W.C., et al. 2015.

LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the

French-Canadian population. Brain J. Neurol. 138(Pt 12): 3503–3519.

doi:10.1093/brain/awv291.

Olesen, J., Gliemann, L., Biensø, R., Schmidt, J., Hellsten, Y., and Pilegaard, H. 2014. Exercise

training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle

of aged men. J. Physiol. 592(8): 1873–1886. doi:10.1113/jphysiol.2013.270256.

Olesen, J., Kiilerich, K., and Pilegaard, H. 2010. PGC-1α-mediated adaptations in skeletal muscle.

Pflüg. Arch. - Eur. J. Physiol. 460(1): 153–162. doi:10.1007/s00424-010-0834-0.

Page 40 of 55



Draft

41

Perez-Schindler, J., Summermatter, S., Salatino, S., Zorzato, F., Beer, M., Balwierz, P.J., et al.

2012. The Corepressor NCoR1 Antagonizes PGC-1 and Estrogen-Related Receptor in the

Regulation of Skeletal Muscle Function and Oxidative Metabolism. Mol. Cell. Biol.

32(24): 4913–4924. doi:10.1128/MCB.00877-12.

Perry, C.G.R., and Hawley, J.A. 2018. Molecular Basis of Exercise-Induced Skeletal Muscle

Mitochondrial Biogenesis: Historical Advances, Current Knowledge, and Future

Challenges. Cold Spring Harb. Perspect. Med. 8(9): a029686.

doi:10.1101/cshperspect.a029686.

Perry, C.G.R., Lally, J., Holloway, G.P., Heigenhauser, G.J.F., Bonen, A., and Spriet, L.L. 2010.

Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial

proteins during training in human skeletal muscle: Molecular responses during

mitochondrial biogenesis. J. Physiol. 588(23): 4795–4810.

doi:10.1113/jphysiol.2010.199448.

Philp, A., and Schenk, S. 2013. Unraveling the Complexities of SIRT1-Mediated Mitochondrial

Regulation in Skeletal Muscle: Exerc. Sport Sci. Rev. 41(3): 174–181.

doi:10.1097/JES.0b013e3182956803.

Piantadosi, C.A., Carraway, M.S., Babiker, A., and Suliman, H.B. 2008. Heme Oxygenase-1

Regulates Cardiac Mitochondrial Biogenesis via Nrf2-Mediated Transcriptional Control of

Nuclear Respiratory Factor-1. Circ. Res. 103(11): 1232–1240.

doi:10.1161/01.RES.0000338597.71702.ad.

Piantadosi, C.A., Withers, C.M., Bartz, R.R., MacGarvey, N.C., Fu, P., Sweeney, T.E., et al. 2011.

Heme Oxygenase-1 Couples Activation of Mitochondrial Biogenesis to Anti-inflammatory

Page 41 of 55



Draft

42

Cytokine Expression. J. Biol. Chem. 286(18): 16374–16385.

doi:10.1074/jbc.M110.207738.

Puigserver, P., Wu, Z., Park, C.W., Graves, R., Wright, M., and Spiegelman, B.M. 1998. A cold-

inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92(6):

829–839.

Qiu, L., Luo, Y., and Chen, X. 2018. Quercetin attenuates mitochondrial dysfunction and

biogenesis via upregulated AMPK/SIRT1 signaling pathway in OA rats. Biomed.

Pharmacother. 103: 1585–1591. doi:10.1016/j.biopha.2018.05.003.

Ramachandran, B., Yu, G., and Gulick, T. 2008. Nuclear Respiratory Factor 1 Controls Myocyte

Enhancer Factor 2A Transcription to Provide a Mechanism for Coordinate Expression of

Respiratory Chain Subunits. J. Biol. Chem. 283(18): 11935–11946.

doi:10.1074/jbc.M707389200.

Ramirez-Sanchez, I., Maya, L., Ceballos, G., and Villarreal, F. 2010. (-)-epicatechin activation of

endothelial cell endothelial nitric oxide synthase, nitric oxide, and related signaling

pathways. Hypertens. Dallas Tex 1979 55(6): 1398–1405.

doi:10.1161/HYPERTENSIONAHA.109.147892.

Rangwala, S.M., Wang, X., Calvo, J.A., Lindsley, L., Zhang, Y., Deyneko, G., et al. 2010.

Estrogen-related Receptor γ Is a Key Regulator of Muscle Mitochondrial Activity and

Oxidative Capacity. J. Biol. Chem. 285(29): 22619–22629. doi:10.1074/jbc.M110.125401.

Rayamajhi, N., Kim, S.-K., Go, H., Joe, Y., Callaway, Z., Kang, J.-G., et al. 2013. Quercetin

Induces Mitochondrial Biogenesis through Activation of HO-1 in HepG2 Cells. Oxid.

Med. Cell. Longev. 2013: 1–10. doi:10.1155/2013/154279.

Page 42 of 55



Draft

43

Robinson, M.M., Dasari, S., Konopka, A.R., Johnson, M.L., Manjunatha, S., Esponda, R.R., et al.

2017. Enhanced Protein Translation Underlies Improved Metabolic and Physical

Adaptations to Different Exercise Training Modes in Young and Old Humans. Cell Metab.

25(3): 581–592. doi:10.1016/j.cmet.2017.02.009.

Sasarman, F., Brunel-Guitton, C., Antonicka, H., Wai, T., Shoubridge, E.A., and LSFC

Consortium. 2010. LRPPRC and SLIRP Interact in a Ribonucleoprotein Complex That

Regulates Posttranscriptional Gene Expression in Mitochondria. Mol. Biol. Cell 21(8):

1315–1323. doi:10.1091/mbc.e10-01-0047.

Sasarman, F., Nishimura, T., Antonicka, H., Weraarpachai, W., Shoubridge, E.A., LSFC

Consortium, et al. 2015. Tissue-specific responses to the LRPPRC founder mutation in

French Canadian Leigh Syndrome. Hum. Mol. Genet. 24(2): 480–491.

doi:10.1093/hmg/ddu468.

Scarpulla, R.C. 2008. Transcriptional Paradigms in Mammalian Mitochondrial Biogenesis and

Function. Physiol. Rev. 88(2): 611–638. doi:10.1152/physrev.00025.2007.

Scarpulla, R.C. 2011. Metabolic control of mitochondrial biogenesis through the PGC-1 family

regulatory network. Biochim. Biophys. Acta BBA - Mol. Cell Res. 1813(7): 1269–1278.

doi:10.1016/j.bbamcr.2010.09.019.

Schuler, M., Ali, F., Chambon, C., Duteil, D., Bornert, J.-M., Tardivel, A., et al. 2006. PGC1α

expression is controlled in skeletal muscles by PPARβ, whose ablation results in fiber-type

switching, obesity, and type 2 diabetes. Cell Metab. 4(5): 407–414.

doi:10.1016/j.cmet.2006.10.003.

Page 43 of 55



Draft

44

Schwarz, N.A., Blahnik, Z.J., Prahadeeswaran, S., McKinley-Barnard, S.K., Holden, S.L., and

Waldhelm, A. 2018. (–)-Epicatechin Supplementation Inhibits Aerobic Adaptations to

Cycling Exercise in Humans. Front. Nutr. 5. doi:10.3389/fnut.2018.00132.

Scribbans, T.D., Ma, J.K., Edgett, B.A., Vorobej, K.A., Mitchell, A.S., Zelt, J.G.E., et al. 2014.

Resveratrol supplementation does not augment performance adaptations or fibre-type-

specific responses to high-intensity interval training in humans. Appl. Physiol. Nutr.

Metab. Physiol. Appl. Nutr. Metab. 39(11): 1305–1313. doi:10.1139/apnm-2014-0070.

Shapiro, T.A., Fahey, J.W., Dinkova-Kostova, A.T., Holtzclaw, W.D., Stephenson, K.K., Wade,

K.L., et al. 2006. Safety, tolerance, and metabolism of broccoli sprout glucosinolates and

isothiocyanates: a clinical phase I study. Nutr. Cancer 55(1): 53–62.

doi:10.1207/s15327914nc5501_7.

Smiles, W.J., and Camera, D.M. 2018. The guardian of the genome p53 regulates exercise-induced

mitochondrial plasticity beyond organelle biogenesis. Acta Physiol. 222(3): e13004.

doi:10.1111/apha.13004.

Somerville, V., Bringans, C., and Braakhuis, A. 2017. Polyphenols and Performance: A Systematic

Review and Meta-Analysis. Sports Med. 47(8): 1589–1599. doi:10.1007/s40279-017-

0675-5.

Sun, C., Yang, C., Xue, R., Li, S., Zhang, T., Pan, L., et al. 2015. Sulforaphane alleviates muscular

dystrophy in mdx mice by activation of Nrf2. J. Appl. Physiol. 118(2): 224–237.


Taub, P.R., Ramirez-Sanchez, I., Ciaraldi, T.P., Gonzalez-Basurto, S., Coral-Vazquez, R., Perkins,

G., et al. 2013. Perturbations in skeletal muscle sarcomere structure in patients with heart

Page 44 of 55



Draft

45

failure and Type 2 diabetes: restorative effects of (−)-epicatechinrich cocoa. Clin. Sci.

125(8): 383–389. doi:10.1042/CS20130023.

Taub, P.R., Ramirez-Sanchez, I., Ciaraldi, T.P., Perkins, G., Murphy, A.N., Naviaux, R., et al.

2012. Alterations in Skeletal Muscle Indicators of Mitochondrial Structure and Biogenesis

in Patients with Type 2 Diabetes and Heart Failure: Effects of Epicatechin Rich Cocoa.

Clin. Transl. Sci. 5(1): 43–47. doi:10.1111/j.1752-8062.2011.00357.x.

Taub, P.R., Ramirez-Sanchez, I., Patel, M., Higginbotham, E., Moreno-Ulloa, A., Román-Pintos,

L.M., et al. 2016. Beneficial effects of dark chocolate on exercise capacity in sedentary

subjects: underlying mechanisms. A double blind, randomized, placebo controlled trial.

Food Funct. 7(9): 3686–3693. doi:10.1039/C6FO00611F.

Tebay, L.E., Robertson, H., Durant, S.T., Vitale, S.R., Penning, T.M., Dinkova-Kostova, A.T., and

Hayes, J.D. 2015. Mechanisms of activation of the transcription factor Nrf2 by redox

stressors, nutrient cues, and energy status and the pathways through which it attenuates

degenerative disease. Free Radic. Biol. Med. 88: 108–146.

doi:10.1016/j.freeradbiomed.2015.06.021.

Varela, C.E., Rodriguez, A., Romero-Valdovinos, M., Mendoza-Lorenzo, P., Mansour, C.,

Ceballos, G., et al. 2017. Browning effects of (-)-epicatechin on adipocytes and white

adipose tissue. Eur. J. Pharmacol. 811: 48–59. doi:10.1016/j.ejphar.2017.05.051.

Vechetti-Junior, I.J., Bertaglia, R.S., Fernandez, G.J., de Paula, T.G., de Souza, R.W.A., Moraes,

L.N., et al. 2016. Aerobic Exercise Recovers Disuse-induced Atrophy Through the

Stimulus of the LRP130/PGC-1α Complex in Aged Rats. J. Gerontol. A. Biol. Sci. Med.

Sci. 71(5): 601–609. doi:10.1093/gerona/glv064.

Page 45 of 55



Draft

46

Wang, L., Liu, J., Saha, P., Huang, J., Chan, L., Spiegelman, B., and Moore, D.D. 2005. The

orphan nuclear receptor SHP regulates PGC-1alpha expression and energy production in

brown adipocytes. Cell Metab. 2(4): 227–238. doi:10.1016/j.cmet.2005.08.010.

Wang, P., Li, C.G., Qi, Z., Cui, D., and Ding, S. 2016. Acute exercise stress promotes Ref1/Nrf2

signalling and increases mitochondrial antioxidant activity in skeletal muscle. Exp.

Physiol. 101(3): 410–420. doi:10.1113/EP085493.

Wang, Y.-X., Lee, C.-H., Tiep, S., Yu, R.T., Ham, J., Kang, H., and Evans, R.M. 2003.

Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent

obesity. Cell 113(2): 159–170.

Wang, Y.-X., Zhang, C.-L., Yu, R.T., Cho, H.K., Nelson, M.C., Bayuga-Ocampo, C.R., et al.

2004. Regulation of Muscle Fiber Type and Running Endurance by PPARδ. PLoS Biol.

2(10): e294. doi:10.1371/journal.pbio.0020294.

Watt, M.J., Southgate, R.J., Holmes, A.G., and Febbraio, M.A. 2004. Suppression of plasma free

fatty acids upregulates peroxisome proliferator-activated receptor (PPAR) α and δ and

PPAR coactivator 1α in human skeletal muscle, but not lipid regulatory genes. J. Mol.

Endocrinol. 33(2): 533–544. doi:10.1677/jme.1.01499.

Whitman, S.A., Long, M., Wondrak, G.T., Zheng, H., and Zhang, D.D. 2013. Nrf2 modulates

contractile and metabolic properties of skeletal muscle in streptozotocin-induced diabetic

atrophy. Exp. Cell Res. 319(17): 2673–2683. doi:10.1016/j.yexcr.2013.07.015.

Williams, C.B., Hughes, M.C., Edgett, B.A., Scribbans, T.D., Simpson, C.A., Perry, C.G.R., and

Gurd, B.J. 2014. An examination of resveratrol’s mechanisms of action in human tissue:

impact of a single dose in vivo and dose responses in skeletal muscle ex vivo. PloS One

9(7): e102406. doi:10.1371/journal.pone.0102406.

Page 46 of 55



Draft

47

Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., et al. 1999.

Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic

coactivator PGC-1. Cell 98(1): 115–124. doi:10.1016/S0092-8674(00)80611-X.

Zhang, H.Q., Chen, S.Y., Wang, A.S., Yao, A.J., Fu, J.F., Zhao, J.S., et al. 2016. Sulforaphane

induces adipocyte browning and promotes glucose and lipid utilization. Mol. Nutr. Food

Res. 60(10): 2185–2197. doi:10.1002/mnfr.201500915.

Page 47 of 55



Draft

48

Figure captions

Figure 1. Regulation of Nrf2 nuclear import and Nrf2 – mediated induction of nuclear-encoded

gene transcription. Disruption of Nrf2’s inhibitory interaction with Keap1 by ROS and NO, direct

phosphorylation of Nrf2 by AMPK, and inactivating phosphorylation of the Nrf2 inhibitor GSK-

3β by AMPK, MAPK, PI3K/Akt, and mTOR promotes translocation of Nrf2 from the cytosol to

the nucleus. Nuclear Nrf2 forms an obligatory heterodimer with small MAF proteins to bind AREs

on the promoters of genes encoding antioxidant and detoxification enzymes, Nrf2 protein, and

NRF-1. Note: Akt; protein kinase B: AMP: adenosine monophosphate; AMPK: AMP activated

protein kinase; ARE: antioxidant response element; GSK-3β: glycogen synthase kinase-3 beta;

Keap1: Kelch-like ECH-associated protein; MAF: small musculoaponeurotic fibrosarcoma

proteins; MAPK: mitogen-activated protein kinases; mTOR: mammalian target of rapamycin; NO:

nitric oxide; NRF-1: nuclear respiratory factor-1; Nrf2: nuclear factor erythroid 2-related factor 2;

PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species.

Figure 2. Post-translational control of ERRγ protein activity, transcriptional activation

of ERRγ gene expression, and ERRγ – mediated induction of nuclear-encoded gene transcription.

Phosphorylation of ERRγ by ERK/MAPK (and potentially by additional exercise-related

signalling proteins) increases the transcriptional activity of ERRγ protein whereas inactivating

phosphorylation by Akt promotes nuclear export of ERRγ. In the nucleus, ERRγ forms a

transcriptional activation complex with PGC-1α and other co-activators to binds ERREs on the

promoters of genes encoding NEMPs and PGC-1α. The ERRγ gene itself is highly inducible and

responsive to various exercise-related stimuli (e.g. ER stress, hypoxia, cAMP production). Note:

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Dotted lines indicate uncertainty regarding the subcellular compartment where the post-

translational modification depicted occurs. Akt: protein kinase B; ATF-6α: activating transcription

factor 6-alpha; cAMP: cyclic adenosine monophosphate; CREB: cAMP response element-binding

protein; ER: endoplasmic reticulum; ERK: extracellular-signal regulated kinases; ERRγ: estrogen-

related receptor gamma; ERRE: estrogen related receptor response element; HIF-1α: hypoxia-

inducible factor 1-alpha: MAPK: mitogen activated protein kinases; NEMPs: nuclear-encoded

mitochondrial proteins; PGC-1α: peroxisome proliferator- activated receptor gamma coactivator-

1 alpha; PKA: protein kinase A; TC: transcriptional co-activator.

Figure 3. Post-translational control of PPARβ protein activity and PPARβ - mediated induction

of nuclear- encoded gene transcription. Phosphorylation of PPARβ protein by AMPK, ERK1/2,

p38 MAPK, and PKA increases PPARβ’s transcriptional activity. In the nucleus, PPARβ

heterodimerizes with RARs to bind PPREs on the promoters of genes encoding PGC-1α, NRF-1,

NEMPs. Cooperation between PPARβ, AMPK, and MEF2A leads to an increase in the expression

of LDHB and PPARβ itself, whereas Sp1 mediates the PPARβ - induced increase in SIRT1 gene

expression. The physical interaction between PPARβ and PGC-1α stabilizes and protects PGC-1α

from ubiquitination and proteasomal degradation. Note: Dotted lines indicate uncertainty

surrounding the subcellular compartment where the post-translational modification and/or protein-

protein interaction depicted occurs. AMP: adenosine monophosphate; AMPK: AMP activated

protein kinase; ERK1/2: extracellular-signal regulated kinase 1/2; LDHB: lactate dehydrogenase

B; MEF2A: myocyte enhancer factor 2A; NEMPs: nuclear-encode mitochondrial proteins; NRF-

1: nuclear respiratory factor-1; PGC-1α: peroxisome proliferator-activated receptor gamma

coactivator-1 alpha; PPARβ: peroxisome proliferator-activated receptor beta; PKA: protein kinase

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A; PPRE: PPAR response element; RAR: retinoic acid receptor; ROS: reactive oxygen species;

SIRT1: sirtuin 1; Sp1: transcription factor Sp1.

Figure 4. Post-translational control of LRP130 protein activity, transcriptional activation of

LRP130 gene expression, and LRP130 actions in the nucleus and mitochondria. In the nucleus,

LRP130 complexes with PGC-1α to regulate PGC-1α’s co-activator activity and knockdown of

PGC-1α/β reduces LRP130 gene expression. In the mitochondria, LRP130 is deacetylated by

SIRT3 and interacts with POLRMT. LRP130 stabilizes mRNAs via direct RNA binding in the

nucleus or as part of a ribonucleoprotein complex with SLIRP in the mitochondria. Note: PGC-

1α/β: peroxisome proliferator- activated receptor gamma coactivator-1 alpha/beta; MEPs:

mitochondrial-encoded proteins; NEMPs: nuclear-encoded mitochondrial proteins; POLRMT:

mitochondrial RNA polymerase; SIRT3: sirtuin 3; SLIRP: SRA stem-loop-interacting RNA-

binding protein; TF: transcription factor.

Figure 5. Redundancies in the transcriptional and post-transcriptional control of mitochondrial

biogenesis by PGC-1α, Nrf2, ERRγ, PPARβ, and LRP130. Note: See Figure legends 1-4 and

manuscript text for abbreviation definitions. Dotted lines indicate uncertainty surrounding the

subcellular compartment where the post-translational modification and/or protein-protein

interaction depicted occurs.

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Figure 1. Regulation of Nrf2 nuclear import and Nrf2 – mediated induction of nuclear-encoded gene transcription. Disruption of Nrf2’s inhibitor interaction with Keap1 by ROS and NO, direct phosphorylation of Nrf2 by AMPK, and inactivating phosphorylation of the Nrf2 inhibitor GSK-3β by AMPK, MAPK, PI3K/Akt, and

mTOR promotes translocation of Nrf2 from the cytosol to the nucleus. Nuclear Nrf2 forms an obligatory heterodimer with small Maf proteins to bind AREs on the promoters of genes encoding antioxidant and

detoxification enzymes, Nrf2 protein, and NRF-1. Note: Akt; protein kinase B: AMP: adenosine monophosphate; AMPK: AMP activated protein kinase; ARE: antioxidant response element; GSK-3β:

glycogen synthase kinase-3 beta; Keap1: Kelch-like ECH-associated protein; MAF: small musculoaponeurotic fibrosarcoma proteins; MAPK: mitogen-activated protein kinases; mTOR: mammalian target of rapamycin;

NO: nitric oxide; NRF-1: nuclear respiratory factor-1; Nrf2: nuclear factor erythroid 2-related factor 2; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species.

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Figure 2. Post-translational control of ERRγ protein activity, transcriptional activation of ERRγ gene expression, and ERRγ – mediated induction of nuclear-encoded gene transcription. Phosphorylation of ERRγ by ERK/MAPK (and potentially by additional exercise-related signalling proteins) increases the transcriptional

activity of ERRγ protein whereas inactivating phosphorylation by Akt promotes nuclear export of ERRγ. In the nucleus, ERRγ forms a transcriptional activation complex with PGC-1α and other co-activators to binds

ERREs on the promoters of genes encoding NEMPs and PGC-1α. The ERRγ gene itself is highly inducible and responsive to various exercise-related stimuli (e.g. ER stress, hypoxia, cAMP production). Note: Dotted lines

indicate uncertainty regarding the subcellular compartment where the post-translational modification depicted occurs. Akt: protein kinase B; ATF-6α: activating transcription factor 6-alpha; cAMP: cyclic

adenosine monophosphate; CREB: cAMP response element-binding protein; ER: endoplasmic reticulum; ERK: extracellular-signal regulated kinases; ERRγ: estrogen-related receptor gamma; ERRE: estrogen

related receptor response element; HIF-1α: hypoxia- inducible factor 1-alpha: MAPK: mitogen activated protein kinases; NEMPs: nuclear-encoded mitochondrial proteins; PGC-1α: peroxisome proliferator-

activated receptor gamma coactivator-1 alpha; PKA: protein kinase A; TC: transcriptional co-activator.

337x189mm (300 x 300 DPI)

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Figure 3. Post-translational control of PPARβ protein activity and PPARβ - mediated induction of nuclear- encoded gene transcription. Phosphorylation of PPARβ protein by AMPK, ERK1/2, p38 MAPK, and PKA

increases PPARβ’s transcriptional activity. In the nucleus, PPARβ heterodimerizes with RARs to bind PPREs on the promoters of genes encoding PGC-1α, NRF-1, NEMPs. Cooperation between PPARβ, AMPK, and MEF2A leads to an increase in the expression of LDHB and PPARβ itself, whereas Sp1 mediates the PPARβ - induced

increase in SIRT1 gene expression. The physical interaction between PPARβ and PGC-1α stabilizes and protects PGC-1α from ubiquitination and proteasomal degradation. Note: Dotted lines indicate uncertainty surrounding the subcellular compartment where the post-translational modification and/or protein-protein

interaction depicted occurs. AMP: adenosine monophosphate; AMPK: AMP activated protein kinase; ERK1/2: extracellular-signal regulated kinase 1/2; LDHB: lactate dehydrogenase B; MEF2A: myocyte enhancer factor

2A; NEMPs: nuclear-encode mitochondrial proteins; NRF-1: nuclear respiratory factor-1; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator-1 alpha; PPARβ: peroxisome proliferator-

activated receptor beta; PKA: protein kinase A; PPRE: PPAR response element; RAR: retinoic acid receptor; ROS: reactive oxygen species; SIRT1: sirtuin 1; Sp1: transcription factor Sp1.

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Figure 4. Post-translational control of LRP130 protein activity, transcriptional activation of LRP130 gene expression, and LRP130 actions in the nucleus and mitochondria. In the nucleus, LRP130 complexes with

PGC-1α to regulate PGC-1α’s co-activator activity and knockdown of PGC-1α/β reduces LRP130 gene expression. In the mitochondria, LRP130 is deacetylated by SIRT3 and interacts with POLRMT. LRP130

stabilizes mRNAs via direct RNA binding in the nucleus or as part of a ribonucleoprotein complex with SLIRP in the mitochondria. Note: PGC-1α/β: peroxisome proliferator- activated receptor gamma coactivator-1 alpha/beta; MEPs: mitochondrial-encoded proteins; NEMPs: nuclear-encoded mitochondrial proteins;

POLRMT: mitochondrial RNA polymerase; SIRT3: sirtuin 3; SLIRP: SRA stem-loop-interacting RNA-binding protein; TF: transcription factor.

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Figure 5. Redundancies in the transcriptional and post-transcriptional control of mitochondrial biogenesis by PGC-1α, Nrf2, ERRγ, PPARβ, and LRP130. Note: See Figure legends 1-4 and manuscript text for abbreviation

definitions. Dotted lines indicate uncertainty surrounding the subcellular compartment where the post-translational modification and/or protein-protein interaction depicted occurs.

337x189mm (300 x 300 DPI)

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