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

2020 ◽  
Vol 45 (1) ◽  
pp. 11-23 ◽  
Author(s):  
Hashim Islam ◽  
David A. Hood ◽  
Brendon J. Gurd
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Respiratory Function ◽  
Human Skeletal Muscle ◽  
Ppar Gamma ◽  
Master Regulator ◽  
Mechanistic Insight ◽  
Simplistic Notion ◽  
Exercise Induced ◽  
Insight Into

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.

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

2019 ◽  
Author(s):  
Cesare Granata ◽  
Rodrigo S.F. Oliveira ◽  
Jonathan P. Little ◽  
David J. Bishop
Keyword(s):  
Skeletal Muscle ◽  
Protein Content ◽  
Mitochondrial Biogenesis ◽  
Exercise Intensity ◽  
High Intensity ◽  
Human Skeletal Muscle ◽  
Interval Training ◽  
High Intensity Interval Training ◽  
High Intensity Interval ◽  
Exercise Induced

ABSTRACTExercise-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 if 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 post, and 3h after a session of 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 were 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-p53Ser15 and p-ACCSer79, 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 if this loss relates to the decrease in relative exercise intensity, habituation to the same exercise stimulus, or a combination of both.

Reduced carbohydrate availability enhances exercise-induced p53 signaling in human skeletal muscle: implications for mitochondrial biogenesis

2013 ◽  
Vol 304 (6) ◽  
pp. R450-R458 ◽  
Author(s):  
Jonathan D. Bartlett ◽  
Jari Louhelainen ◽  
Zafar Iqbal ◽  
Andrew J. Cochran ◽  
Martin J. Gibala ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Repeated Measures ◽  
Human Skeletal Muscle ◽  
Vastus Lateralis ◽  
Oxidative Capacity ◽  
Pyruvate Dehydrogenase Kinase ◽  
Repeated Measures Design ◽  
P53 Signaling ◽  
Exercise Induced

The mechanisms that regulate the enhanced skeletal muscle oxidative capacity observed when training with reduced carbohydrate (CHO) availability are currently unknown. The aim of the present study was to test the hypothesis that reduced CHO availability enhances p53 signaling and expression of genes associated with regulation of mitochondrial biogenesis and substrate utilization in human skeletal muscle. In a repeated-measures design, muscle biopsies (vastus lateralis) were obtained from eight active males before and after performing an acute bout of high-intensity interval running with either high (HIGH) or low CHO availability (LOW). Resting muscle glycogen (HIGH, 467 ± 19; LOW, 103 ± 9 mmol/kg dry wt) was greater in HIGH compared with LOW ( P < 0.05). Phosphorylation (P-) of ACCSer79 (HIGH, 1.4 ± 0.4; LOW, 2.9 ± 0.9) and p53Ser15 (HIGH, 0.9 ± 0.4; LOW, 2.6 ± 0.8) was higher in LOW immediately postexercise and 3 h postexercise, respectively ( P < 0.05). Before and 3 h postexercise, mRNA content of pyruvate dehydrogenase kinase 4, mitochondrial transcription factor A, cytochrome- c oxidase IV, and PGC-1α were greater in LOW compared with HIGH ( P < 0.05), whereas carnitine palmitoyltransferase-1 showed a trend toward significance ( P = 0.09). However, only PGC-1α expression was increased by exercise ( P < 0.05), where three-fold increases occurred independently of CHO availability. We conclude that the exercise-induced increase in p53 phosphorylation is enhanced in conditions of reduced CHO availability, which may be related to upstream signaling through AMPK. Given the emergence of p53 as a molecular regulator of mitochondrial biogenesis, such nutritional modulation of contraction-induced p53 activation has implications for both athletic and clinical populations.

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

2017 ◽  
Vol 5 (5) ◽  
pp. e13155 ◽  
Author(s):  
Debasmita Bhattacharya ◽  
Mia Ydfors ◽  
Meghan C. Hughes ◽  
Jessica Norrbom ◽  
Christopher G. R. Perry ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Human Skeletal Muscle ◽  
Transcriptional Corepressor ◽  
Exercise Induced

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

2020 ◽  
Vol 318 (2) ◽  
pp. E224-E236 ◽  
Author(s):  
Cesare Granata ◽  
Rodrigo S. F. Oliveira ◽  
Jonathan P. Little ◽  
David J. Bishop
Keyword(s):  
Skeletal Muscle ◽  
Protein Content ◽  
Mitochondrial Biogenesis ◽  
Exercise Intensity ◽  
High Intensity ◽  
Human Skeletal Muscle ◽  
Interval Training ◽  
High Intensity Interval Training ◽  
High Intensity Interval ◽  
Exercise Induced

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.

Does impaired mitochondrial function affect insulin signaling and action in cultured human skeletal muscle cells?

2008 ◽  
Vol 294 (1) ◽  
pp. E97-E102 ◽  
Author(s):  
Audrey E. Brown ◽  
Matthias Elstner ◽  
Stephen J. Yeaman ◽  
Douglass M. Turnbull ◽  
Mark Walker
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Mitochondrial Respiration ◽  
Respiratory Function ◽  
Insulin Action ◽  
Human Skeletal Muscle ◽  
Human Skeletal Muscle Cells ◽  
Basal Glucose Uptake

Insulin-resistant type 2 diabetic patients have been reported to have impaired skeletal muscle mitochondrial respiratory function. A key question is whether decreased mitochondrial respiration contributes directly to the decreased insulin action. To address this, a model of impaired cellular respiratory function was established by incubating human skeletal muscle cell cultures with the mitochondrial inhibitor sodium azide and examining the effects on insulin action. Incubation of human skeletal muscle cells with 50 and 75 μM azide resulted in 48 ± 3% and 56 ± 1% decreases, respectively, in respiration compared with untreated cells mimicking the level of impairment seen in type 2 diabetes. Under conditions of decreased respiratory chain function, insulin-independent (basal) glucose uptake was significantly increased. Basal glucose uptake was 325 ± 39 pmol/min/mg (mean ± SE) in untreated cells. This increased to 669 ± 69 and 823 ± 83 pmol/min/mg in cells treated with 50 and 75 μM azide, respectively (vs. untreated, both P < 0.0001). Azide treatment was also accompanied by an increase in basal glycogen synthesis and phosphorylation of AMP-activated protein kinase. However, there was no decrease in glucose uptake following insulin exposure, and insulin-stimulated phosphorylation of Akt was normal under these conditions. GLUT1 mRNA expression remained unchanged, whereas GLUT4 mRNA expression increased following azide treatment. In conclusion, under conditions of impaired mitochondrial respiration there was no evidence of impaired insulin signaling or glucose uptake following insulin exposure in this model system.

scholarly journals Endurance training reduces the contraction-induced interleukin-6 mRNA expression in human skeletal muscle

2004 ◽  
Vol 287 (6) ◽  
pp. E1189-E1194 ◽  
Author(s):  
Christian P. Fischer ◽  
Peter Plomgaard ◽  
Anne K. Hansen ◽  
Henriette Pilegaard ◽  
Bengt Saltin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Muscle Glycogen ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Glycogen Content ◽  
Knee Extensor ◽  
Exercise Induced ◽  
Response To Exercise ◽  
Resting Muscle

Contracting skeletal muscle expresses large amounts of IL-6. Because 1) IL-6 mRNA expression in contracting skeletal muscle is enhanced by low muscle glycogen content, and 2) IL-6 increases lipolysis and oxidation of fatty acids, we hypothesized that regular exercise training, associated with increased levels of resting muscle glycogen and enhanced capacity to oxidize fatty acids, would lead to a less-pronounced increase of skeletal muscle IL-6 mRNA in response to acute exercise. Thus, before and after 10 wk of knee extensor endurance training, skeletal muscle IL-6 mRNA expression was determined in young healthy men ( n = 7) in response to 3 h of dynamic knee extensor exercise, using the same relative workload. Maximal power output, time to exhaustion during submaximal exercise, resting muscle glycogen content, and citrate synthase and 3-hydroxyacyl-CoA dehydrogenase enzyme activity were all significantly enhanced by training. IL-6 mRNA expression in resting skeletal muscle did not change in response to training. However, although absolute workload during acute exercise was 44% higher ( P < 0.05) after the training period, skeletal muscle IL-6 mRNA content increased 76-fold ( P < 0.05) in response to exercise before the training period, but only 8-fold ( P < 0.05, relative to rest and pretraining) in response to exercise after training. Furthermore, the exercise-induced increase of plasma IL-6 ( P < 0.05, pre- and posttraining) was not higher after training despite higher absolute work intensity. In conclusion, the magnitude of the exercise-induced IL-6 mRNA expression in contracting human skeletal muscle was markedly reduced by 10 wk of training.

Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle

2015 ◽  
Vol 118 (8) ◽  
pp. 971-979 ◽  
Author(s):  
Andreas Buch Møller ◽  
Mikkel Holm Vendelbo ◽  
Britt Christensen ◽  
Berthil Forrest Clasen ◽  
Ann Mosegaard Bak ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Physical Exercise ◽  
Light Chain ◽  
Human Skeletal Muscle ◽  
Transgenic Animal ◽  
Dependent Manner ◽  
Healthy Humans ◽  
Transgenic Animal Models ◽  
Exercise Induced

Data from transgenic animal models suggest that exercise-induced autophagy is critical for adaptation to physical training, and that Unc-51 like kinase-1 (ULK1) serves as an important regulator of autophagy. Phosphorylation of ULK1 at Ser555 stimulates autophagy, whereas phosphorylation at Ser757 is inhibitory. To determine whether exercise regulates ULK1 phosphorylation in humans in vivo in a nutrient-dependent manner, we examined skeletal muscle biopsies from healthy humans after 1-h cycling exercise at 50% maximal O2 uptake on two occasions: 1) during a 36-h fast, and 2) during continuous glucose infusion at 0.2 kg/h. Physical exercise increased ULK1 phosphorylation at Ser555 and decreased lipidation of light chain 3B. ULK1 phosphorylation at Ser555 correlated positively with AMP-activated protein kinase-α Thr172 phosphorylation and negatively with light chain 3B lipidation. ULK1 phosphorylation at Ser757 was not affected by exercise. Fasting increased ULK1 and p62 protein expression, but did not affect exercise-induced ULK1 phosphorylation. These data demonstrate that autophagy signaling is activated in human skeletal muscle after 60 min of exercise, independently of nutritional status, and suggest that initiation of autophagy constitutes an important physiological response to exercise in humans.

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