Exercise-induced Mitochondrial Biogenesis Research Articles

Role of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) in regulating mitochondrial energy effciency in skeletal muscle

Previous studies have shown that exercise training improves mitochondrial energy effciency in skeletal muscle, but the molecular mechanism is unclear. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) is a transcriptional co-activator that coordinately regulates exercise-induced mitochondrial biogenesis and quality control. This study aimed to test the hypothesis that PGC-1a is involved in the improvement of mitochondrial energy effciency in skeletal muscle by using a skeletal muscle-specific PGC-1a overexpression mouse model. Ten to twelve-week-old skeletal muscle-specific PGC-1a transgenic mice (MCK-PGC-1a) and their wildtype littermates (WT) were used. Protein levels of oxidative phosphorylation (OXPHOS) subunits in skeletal muscle were determined by Western blot analysis. The rate of O2 consumption ( JO2) and ATP production ( JATP) in isolated mitochondria from skeletal muscle were evaluated using high-resolution respirometry and fluorometry, respectively, and mitochondrial energy effciency (ATP produced per O2 consumed, or P/O) was calculated. Overexpression of PGC-1a in skeletal muscle did not affect body weights and muscle weights. Consistent with previous studies, MCK-PGC-1a mice had significantly higher OXPHOS protein content than WT mice. On the other hand, JO2, JATP, and P/O in isolated muscle mitochondria were not different between genotypes. Our results suggest that exercise training-induced improvement in muscle mitochondrial energy effciency is not mediated by PGC-1a. This research is supported by NIH grant DK107397 to K.F. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exercise-induced fumarate accumulation: a potential mediator of mitochondrial biogenesis in mammalian skeletal muscle

Endurance exercise is known to induce mitochondrial biogenesis in mammalian skeletal muscles. However, the exact mechanism via which this exercise-induced mitochondria biogenesis occurs remains unclear. Extraneous physical activity induces several adaptive metabolic changes in the skeletal muscle including the activation purine nucleotide cycle (PNC) and utilization of amino acid as fuel sources. These metabolic adaptations are likely to cause accumulation of intra-muscular fumarate that might be a key mediator of exercise-induced mitochondrial biogenesis. This is because high intracellular levels of fumarate cause irreversible succination of Keap1, which leads to activation of nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) signalling. Activation of Nrf2 signalling in turn is known to play a role in contraction-induced mitochondria biogenesis. Accordingly, it is possible that therapeutic strategies that enhance skeletal muscle fumarate levels might potentially enhance muscle mitochondrial biogenesis, content and overall physical performance.

TAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A

Mitochondria are energy-generating organelles and mitochondrial biogenesis is stimulated to meet energy requirements in response to extracellular stimuli, including exercise. However, the mechanisms underlying mitochondrial biogenesis remain unknown. Here, we demonstrate that transcriptional coactivator with PDZ-binding motif (TAZ) stimulates mitochondrial biogenesis in skeletal muscle. In muscle-specific TAZ-knockout (mKO) mice, mitochondrial biogenesis, respiratory metabolism, and exercise ability were decreased compared to wild-type mice. Mechanistically, TAZ stimulates the translation of mitochondrial transcription factor A via Ras homolog enriched in brain (Rheb)/Rheb like 1 (Rhebl1)-mTOR axis. TAZ stimulates Rhebl1 expression via TEA domain family transcription factor. Rhebl1 introduction by adeno-associated virus or mTOR activation recovered mitochondrial biogenesis in mKO muscle. Physiologically, mKO mice did not stimulate exercise-induced mitochondrial biogenesis. Collectively, our results suggested that TAZ is a novel stimulator for mitochondrial biogenesis and exercise-induced muscle adaptation.

Transcription Factor Movement and Exercise-Induced Mitochondrial Biogenesis in Human Skeletal Muscle: Current Knowledge and Future Perspectives.

In response to exercise, the oxidative capacity of mitochondria within skeletal muscle increases through the coordinated expression of mitochondrial proteins in a process termed mitochondrial biogenesis. Controlling the expression of mitochondrial proteins are transcription factors—a group of proteins that regulate messenger RNA transcription from DNA in the nucleus and mitochondria. To fulfil other functions or to limit gene expression, transcription factors are often localised away from DNA to different subcellular compartments and undergo rapid movement or accumulation only when required. Although many transcription factors involved in exercise-induced mitochondrial biogenesis have been identified, numerous conflicting findings and gaps exist within our knowledge of their subcellular movement. This review aims to summarise and provide a critical analysis of the published literature regarding the exercise-induced movement of transcription factors involved in mitochondria biogenesis in skeletal muscle.

Mass-spectrometry-based proteomics reveals mitochondrial supercomplexome plasticity

Mitochondrial respiratory complex subunits assemble in supercomplexes. Studies of supercomplexes have typically relied upon antibody-based quantification, often limited to a single subunit per respiratory complex. To provide a deeper insight into mitochondrial and supercomplex plasticity, we combine native electrophoresis and mass spectrometry to determine the supercomplexome of skeletal muscle from sedentary and exercise-trained mice. We quantify 422 mitochondrial proteins within 10 supercomplex bands in which we show the debated presence of complexes II and V. Exercise-induced mitochondrial biogenesis results in non-stoichiometric changes in subunits and incorporation into supercomplexes. We uncover the dynamics of supercomplex-related assembly proteins and mtDNA-encoded subunits after exercise. Furthermore, exercise affects the complexing of Lactb, an obesity-associated mitochondrial protein, and ubiquinone biosynthesis proteins. Knockdown of ubiquinone biosynthesis proteins leads to alterations in mitochondrial respiration. Our approach can be applied to broad biological systems. In this instance, comprehensively analyzing respiratory supercomplexes illuminates previously undetectable complexity in mitochondrial plasticity.

Distinct Roles of Zmynd17 and PGC1α in Mitochondrial Quality Control and Biogenesis in Skeletal Muscle.

Maintaining skeletal muscle mitochondrial quality is important not only for muscle activity but also for systemic metabolism. Exercise has long been recognized to have a positive impact on muscle mitochondrial quality. Although exercise triggers various changes in the mitochondrial dynamics, its molecular basis remains to be elucidated. We have previously reported that inactivation of the muscle-specific protein, zinc finger MYND domain-containing protein 17 (Zmynd17), results in mitochondrial abnormalities. To investigate the link between Zmynd17 activity and exercise-induced mitochondrial maintenance, we observed the effect of consecutive exercise on the mitochondrial quality in Zmynd17-deficient muscles. Zmynd17-deficient mice displayed abnormal mitochondrial morphology in limb muscles, which remarkably improved upon voluntary exercise. Interestingly, morphological abnormalities in mitochondria were even more apparent when PGC1α, a regulator of exercise-induced mitochondrial biogenesis, was overexpressed in Zmynd17-KO limb muscle. These abnormalities were also ameliorated by voluntary exercise. Our results show that neither the effect of consecutive exercise on mitochondrial quality nor PGC1α-induced mitochondrial biogenesis are mediated through Zmynd17 activity, thereby suggesting the existence of a complex mechanism of mitochondrial quality control in muscles.

Forty high-intensity interval training sessions blunt exercise-induced changes in the nuclear protein content of PGC-1α and p53 in human skeletal muscle.

Exercise-induced increases in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and p53 protein content in the nucleus mediate the initial phase of exercise-induced mitochondrial biogenesis. Here, we investigated whether exercise-induced increases in these and other markers of mitochondrial biogenesis were altered after 40 sessions of twice-daily high-volume, high-intensity interval training (HVT) in human skeletal muscle. Vastus lateralis muscle biopsies were collected from 10 healthy recreationally active participants before, immediately postexercise, and 3 h after a session of high-intensity interval exercise (HIIE) performed at the same absolute exercise intensity before and after HVT (pre-HVT and post-HVT, respectively). The protein content of common markers of exercise-induced mitochondrial biogenesis was assessed in nuclear- and cytosolic-enriched fractions by immunoblotting; mRNA contents of key transcription factors and mitochondrial genes were assessed by qPCR. Despite exercise-induced increases in PGC-1α, p53, and plant homeodomain finger-containing protein 20 (PHF20) protein content, the phosphorylation of p53 and acetyl-CoA carboxylase (p-p53 Ser15 and p-ACC Ser79, respectively), and PGC-1α mRNA Pre-HVT, no significant changes were observed post-HVT. Forty sessions of twice-daily high-intensity interval training blunted all of the measured exercise-induced molecular events associated with mitochondrial biogenesis that were observed pre-HVT. Future studies should determine whether this loss relates to the decrease in relative exercise intensity, habituation to the same exercise stimulus, or a combination of both.

The impact of acute and chronic exercise on Nrf2 expression in relation to markers of mitochondrial biogenesis in human skeletal muscle.

To examine the relationship between changes in nuclear factor erythroid 2-related factor 2 (Nrf2) expression and markers of mitochondrial biogenesis in acutely and chronically exercised human skeletal muscle. The impact of acute submaximal endurance (END) and supramaximal interval (Tabata) cycling on the upregulation of Nrf2 (and its downstream targets), nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (TFAM) mRNA expression was examined in healthy young males (n = 10). The relationship between changes in citrate synthase (CS) maximal activity and the protein content of Nrf2, heme oxygenase 1 (HO-1), NRF-1, and TFAM was also investigated following 4 weeks of Tabata in a separate group of males (n = 21). Nrf2, NRF-1, and HO-1 mRNA expression increased after acute exercise (p < 0.05), whereas the increase in superoxide dismutase 2 (SOD2) mRNA expression approached significance (p = 0.08). Four weeks of Tabata increased CS activity and Nrf2, NRF-1, and TFAM protein content (p < 0.05), but decreased HO-1 protein content (p < 0.05). Training-induced changes in Nrf2 protein were strongly correlated with NRF-1 (r = 0.63, p < 0.01). When comparing protein content changes between individuals with the largest (HI: + 23%) and smallest (LO: - 1%) observed changes in CS activity (n = 8 each), increases in Nrf2 and TFAM protein content were apparent in the HI group only (p < 0.02) with medium-to-large effect sizes for between-group differences in changes in Nrf2 (ηp2=0.15) and TFAM (ηp2 = 0.12) protein content. Altogether, our findings support a potential role for Nrf2 in exercise-induced mitochondrial biogenesis in human skeletal muscle.

Looking beyond PGC-1α: emerging regulators of exercise-induced skeletal muscle mitochondrial biogenesis and their activation by dietary compounds.

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-1α) appears to be dispensable for the training-induced augmentation of skeletal muscle mitochondrial content and respiratory function. In fact, a number of regulatory proteins have emerged as important players in skeletal muscle mitochondrial biogenesis and many of these proteins share key attributes with PGC-1α. 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. Novelty The existence of redundant pathways leading to mitochondrial biogenesis refutes the simplistic notion of a "master regulator" of mitochondrial biogenesis. Dietary activation of specific pathways may provide greater mechanistic insight into the exercise-induced mitochondrial biogenesis in human skeletal muscle.

A physiological drop in pH decreases mitochondrial respiration, and HDAC and Akt signaling, in L6 myocytes.

Exercise stimulates mitochondrial biogenesis and increases mitochondrial respiratory function and content. However, during high-intensity exercise muscle pH can decrease below pH 6.8 with a concomitant increase in lactate concentration. This drop in muscle pH is associated with reduced exercise-induced mitochondrial biogenesis, while increased lactate may act as a signaling molecule to affect mitochondrial biogenesis. Therefore, in this study we wished to determine the impact of altering pH and lactate concentration in L6 myotubes on genes and proteins known to be involved in mitochondrial biogenesis. We also examined mitochondrial respiration in response to these perturbations. Differentiated L6 myotubes were exposed to normal (pH 7.5)-, low (pH 7.0)-, or high (pH 8.0)-pH media with and without 20 mM sodium l-lactate for 1 and 6 h. Low pH and 20 mM sodium l-lactate resulted in decreased Akt (Ser473) and AMPK (T172) phosphorylation at 1 h compared with controls, while at 6 h the nuclear localization of histone deacetylase 5 (HDAC5) was decreased. When the pH was increased both Akt (Ser473) and AMPK (T172) phosphorylation was increased at 1 h. Overall increased lactate decreased the nuclear content of HDAC5 at 6 h. Exposure to both high- and low-pH media decreased basal mitochondrial respiration, ATP turnover, and maximum mitochondrial respiratory capacity. These data indicate that muscle pH affects several metabolic signaling pathways, including those required for mitochondrial function.

Exercise-induced mitochondrial biogenesis coincides with the expression of mitochondrial translation factors in murine skeletal muscle.

The process of mitochondrial translation, in which mitochondrial (mt)DNA‐encoded genes are translated into proteins, is crucial for mitochondrial function and biogenesis. In each phase, a series of mitochondrial translation factors is required for the synthesis of mtDNA‐encoded mitochondrial proteins. Two mitochondrial initiation factors (mtIF2 and mtIF3), three mitochondrial elongation factors (mtEFTu, mtEFTs, and mtEFG1), one mitochondrial release factor (mtRF1L), and two mitochondrial recycling factors (mtRRF1 and mtRRF2) are mitochondrial translation factors that coordinate each translational phase. Exercise increases both nuclear DNA‐ and mtDNA‐encoded mitochondrial proteins, resulting in mitochondrial biogenesis in skeletal muscles. Therefore, mitochondrial translation factors are likely regulated by exercise; however, it is unclear whether exercise affects mitochondrial translation factors in the skeletal muscles. We investigated whether exercise training comprehensively increases this series of mitochondrial translation factors, as well as mtDNA‐encoded proteins, in the skeletal muscle. Mice were randomly assigned to either the sedentary or exercise group and housed in standard cages with or without a running wheel for 1 and 8 weeks. The expression levels of mitochondrial translation factors in the plantaris and soleus muscles were then measured. Exercise training concomitantly upregulated mitochondrial translation factors and mitochondrial proteins in the plantaris muscle. However, in the soleus muscle, these comprehensive upregulations were not detected. These results indicate that exercise‐induced mitochondrial biogenesis coincides with the upregulation of mitochondrial translation factors.

Exercise-induced mitochondrial biogenesis: is it a key for diseases prevention?

Exercise-induced mitochondrial biogenesis: is it a key for diseases prevention?

Metabolic stress-dependent regulation of the mitochondrial biogenic molecular response to high-intensity exercise in human skeletal muscle.

Low-volume high-intensity exercise training promotes muscle mitochondrial adaptations that resemble those associated with high-volume moderate-intensity exercise training. These training-induced mitochondrial adaptations stem from the cumulative effects of transient transcriptional responses to each acute exercise bout. However, whether metabolic stress is a key mediator of the acute molecular responses to high-intensity exercise is still incompletely understood. Here we show that, by comparing different work-matched low-volume high-intensity exercise protocols, more marked metabolic perturbations were associated with enhanced mitochondrial biogenesis-related muscle mRNA responses. Furthermore, when compared with high-volume moderate-intensity exercise, only the low-volume high-intensity exercise eliciting severe metabolic stress compensated for reduced exercise volume in the induction of mitochondrial biogenic mRNA responses. The present results, besides improving our understanding of the mechanisms mediating exercise-induced mitochondrial biogenesis, may have implications for applied and clinical research that adopts exercise as a means to increase muscle mitochondrial content and function in healthy or diseased individuals. The aim of the present study was to examine the impact of exercise-induced metabolic stress on regulation of the molecular responses promoting skeletal muscle mitochondrial biogenesis. Twelve endurance-trained men performed three cycling exercise protocols characterized by different metabolic profiles in a randomized, counter-balanced order. Specifically, two work-matched low-volume supramaximal-intensity intermittent regimes, consisting of repeated-sprint (RS) and speed endurance (SE) exercise, were employed and compared with a high-volume continuous moderate-intensity exercise (CM) protocol. Vastus lateralis muscle samples were obtained before, immediately after, and 3h after exercise. SE produced the most marked metabolic perturbations as evidenced by the greatest changes in muscle lactate and pH, concomitantly with higher post-exercise plasma adrenaline levels in comparison with RS and CM. Exercise-induced phosphorylation of CaMKII and p38 MAPK was greater in SE than in RS and CM. The exercise-induced PGC-1α mRNA response was higher in SE and CM than in RS, with no difference between SE and CM. Muscle NRF-2, TFAM, MFN2, DRP1 and SOD2 mRNA content was elevated to the same extent by SE and CM, while RS had no effect on these mRNAs. The exercise-induced HSP72 mRNA response was larger in SE than in RS and CM. Thus, the present results suggest that, for a given exercise volume, the initial events associated with mitochondrial biogenesis are modulated by metabolic stress. In addition, high-intensity exercise seems to compensate for reduced exercise volume in the induction of mitochondrial biogenic molecular responses only when the intense exercise elicits marked metabolic perturbations.

Exercise-induced mitochondrial biogenesis in muscle 2

Exercise-induced mitochondrial biogenesis in muscle 2

Exercise-induced mitochondrial biogenesis in muscle 1

Exercise-induced mitochondrial biogenesis in muscle 1

Principles of Exercise Prescription, and How They Influence Exercise-Induced Changes of Transcription Factors and Other Regulators of Mitochondrial Biogenesis.

Physical inactivity represents the fourth leading risk factor for mortality, and it has been linked with a series of chronic disorders, the treatment of which absorbs ~ 85% of healthcare costs in developed countries. Conversely, physical activity promotes many health benefits; endurance exercise in particular represents a powerful stimulus to induce mitochondrial biogenesis, and it is routinely used to prevent and treat chronic metabolic disorders linked with sub-optimal mitochondrial characteristics. Given the importance of maintaining a healthy mitochondrial pool, it is vital to better characterize how manipulating the endurance exercise dose affects cellular mechanisms of exercise-induced mitochondrial biogenesis. Herein, we propose a definition of mitochondrial biogenesis and the techniques available to assess it, and we emphasize the importance of standardizing biopsy timing and the determination of relative exercise intensity when comparing different studies. We report an intensity-dependent regulation of exercise-induced increases in nuclear peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein content, nuclear phosphorylation of p53 (serine 15), and PGC-1α messenger RNA (mRNA), as well as training-induced increases in PGC-1α and p53 protein content. Despite evidence that PGC-1α protein content plateaus within a few exercise sessions, we demonstrate that greater training volumes induce further increases in PGC-1α (and p53) protein content, and that short-term reductions in training volume decrease the content of both proteins, suggesting training volume is still a factor affecting training-induced mitochondrial biogenesis. Finally, training-induced changes in mitochondrial transcription factor A (TFAM) protein content are regulated in a training volume-dependent manner and have been linked with training-induced changes in mitochondrial content.

Principles, insights, and potential pitfalls of the noninvasive determination of muscle oxidative capacity by near-infrared spectroscopy.

Skeletal muscle oxidative capacity is highly plastic, strongly associated with whole-body aerobic capacity (16, 18) and state of health. Loss of muscle oxidative capacity is associated with physical inactivity, aging and chronic disease (17), and has been implicated in the pathophysiology of obesity and diabetes (21). Evaluating these changes has traditionally been limited to invasive or costly assessments (biopsy or ³¹P MRS). To address this, Hamaoka and colleagues developed an innovative, non-invasive approach using near-infrared spectroscopy (NIRS) to quantitatively measure muscle oxygen consumption (mVO₂; 12) and use this to infer muscle oxidative capacity based on the mVO₂ recovery rate constant (k) (23; later modified 26). This technique has been subsequently used to interpret relative differences in oxidative capacity across a wide range of muscles, ages and disease states (Figure 1C). The purpose of this Viewpoint is to open a discussion on the principles, insights and potential pitfalls of using NIRS to measure k and infer muscle oxidative capacity.

Molecular Basis of Exercise-Induced Skeletal Muscle Mitochondrial Biogenesis: Historical Advances, Current Knowledge, and Future Challenges.

We provide an overview of groundbreaking studies that laid the foundation for our current understanding of exercise-induced mitochondrial biogenesis and its contribution to human skeletal muscle fitness. We highlight the mechanisms by which skeletal muscle responds to the acute perturbations in cellular energy homeostasis evoked by a single bout of endurance-based exercise and the adaptations resulting from the repeated demands of exercise training that ultimately promote mitochondrial biogenesis through hormetic feedback loops. Despite intense research efforts to elucidate the cellular mechanisms underpinning mitochondrial biogenesis in skeletal muscle, translating this basic knowledge into improved metabolic health at the population level remains a future challenge.

Decreased transcriptional corepressor p107 is associated with exercise-induced mitochondrial biogenesis in human skeletal muscle.

Increased mitochondrial content is a hallmark of exercise‐induced skeletal muscle remodeling. For this process, considerable evidence underscores the involvement of transcriptional coactivators in mediating mitochondrial biogenesis. However, our knowledge regarding the role of transcriptional corepressors is lacking. In this study, we assessed the association of the transcriptional corepressor Rb family proteins, Rb and p107, with endurance exercise‐induced mitochondrial adaptation in human skeletal muscle. We showed that p107, but not Rb, protein levels decrease by 3 weeks of high‐intensity interval training. This is associated with significant inverse association between p107 and exercise‐induced improved mitochondrial oxidative phosphorylation. Indeed, p107 showed significant reciprocal correlations with the protein contents of representative markers of mitochondrial electron transport chain complexes. These findings in human skeletal muscle suggest that attenuated transcriptional repression through p107 may be a novel mechanism by which exercise stimulates mitochondrial biogenesis following exercise.

Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis.

Endurance exercise, when performed regularly as part of a training program, leads to increases in whole-body and skeletal muscle-specific oxidative capacity. At the cellular level, this adaptive response is manifested by an increased number of oxidative fibers (Type I and IIA myosin heavy chain), an increase in capillarity and an increase in mitochondrial biogenesis. The increase in mitochondrial biogenesis (increased volume and functional capacity) is fundamentally important as it leads to greater rates of oxidative phosphorylation and an improved capacity to utilize fatty acids during sub-maximal exercise. Given the importance of mitochondrial biogenesis for skeletal muscle performance, considerable attention has been given to understanding the molecular cues stimulated by endurance exercise that culminate in this adaptive response. In turn, this research has led to the identification of pharmaceutical compounds and small nutritional bioactive ingredients that appear able to amplify exercise-responsive signaling pathways in skeletal muscle. The aim of this review is to discuss these purported exercise mimetics and bioactive ingredients in the context of mitochondrial biogenesis in skeletal muscle. We will examine proposed modes of action, discuss evidence of application in skeletal muscle in vivo and finally comment on the feasibility of such approaches to support endurance-training applications in humans.