scholarly journals The erythropoietin receptor expressed in skeletal muscle is essential for mitochondrial biogenesis and physiological exercise

2021 ◽  
Author(s):  
Kirsten T. Nijholt ◽  
Laura M. G. Meems ◽  
Willem P. T. Ruifrok ◽  
Alexander H. Maass ◽  
Salva R. Yurista ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Exercise Performance ◽  
Critical Role ◽  
Erythropoietin Receptor ◽  
Voluntary Exercise ◽  
Physiological Adaptation ◽  
Muscle Physiology ◽  
Mitochondrial Content ◽  
Exercise Induced

AbstractErythropoietin (EPO) is a haematopoietic hormone that regulates erythropoiesis, but the EPO-receptor (EpoR) is also expressed in non-haematopoietic tissues. Stimulation of the EpoR in cardiac and skeletal muscle provides protection from various forms of pathological stress, but its relevance for normal muscle physiology remains unclear. We aimed to determine the contribution of the tissue-specific EpoR to exercise-induced remodelling of cardiac and skeletal muscle. Baseline phenotyping was performed on left ventricle and m. gastrocnemius of mice that only express the EpoR in haematopoietic tissues (EpoR-tKO). Subsequently, mice were caged in the presence or absence of a running wheel for 4 weeks and exercise performance, cardiac function and histological and molecular markers for physiological adaptation were assessed. While gross morphology of both muscles was normal in EpoR-tKO mice, mitochondrial content in skeletal muscle was decreased by 50%, associated with similar reductions in mitochondrial biogenesis, while mitophagy was unaltered. When subjected to exercise, EpoR-tKO mice ran slower and covered less distance than wild-type (WT) mice (5.5 ± 0.6 vs. 8.0 ± 0.4 km/day, p < 0.01). The impaired exercise performance was paralleled by reductions in myocyte growth and angiogenesis in both muscle types. Our findings indicate that the endogenous EPO-EpoR system controls mitochondrial biogenesis in skeletal muscle. The reductions in mitochondrial content were associated with reduced exercise capacity in response to voluntary exercise, supporting a critical role for the extra-haematopoietic EpoR in exercise performance.

scholarly journals Mitochondria-targeted antioxidant supplementation augments acute exercise-induced increases in muscle PGC1α mRNA and improves training-induced increases in peak power independent of mitochondrial content and function in untrained middle-aged men

2021 ◽  
Author(s):  
S. C. Broome ◽  
T. Pham ◽  
A. J. Braakhuis ◽  
R. Narang ◽  
H. W. Wang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Mitochondrial Biogenesis ◽  
High Intensity ◽  
Peak Power ◽  
Acute Exercise ◽  
Mitochondrial Content ◽  
High Intensity Interval ◽  
Exercise Induced ◽  
And Function

ABSTRACTThe role of mitochondrial ROS production and signalling in muscle adaptations to exercise training has not been explored in detail. Here we investigated the effect of supplementation with the mitochondria-targeted antioxidant MitoQ on a) the skeletal muscle mitochondrial and antioxidant gene transcriptional response to acute high-intensity exercise and b) skeletal muscle mitochondrial content and function following exercise training. In a randomised, double-blind, placebo-controlled, parallel design study, 23 untrained men (age: 44 ± 7 years, VO2peak: 39.6 ± 7.9 ml/kg/min) were randomised to receive either MitoQ (20 mg/d) or a placebo for 10 days before completing a bout of high-intensity interval exercise (cycle ergometer, 10 × 60 s at VO2peak workload with 75 s rest). Blood samples and vastus lateralis muscle biopsies were collected before exercise and immediately and 3 hours after exercise. Participants then completed high-intensity interval training (HIIT; 3 sessions per week for 3 weeks) and another blood sample and muscle biopsy were collected. MitoQ supplementation augmented acute exercise-induced increases in skeletal muscle mRNA expression of the major regulator of proteins involved in mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α). Despite this, training-induced increases in skeletal muscle mitochondrial content were unaffected by MitoQ supplementation. HIIT-induced increases in VO2peak and 20 km time trial performance were also unaffected by MitoQ while MitoQ augmented training-induced increases in peak power achieved during the VO2peak test. These data suggest that MitoQ supplementation enhances the effect of training on peak power, which may be related to the augmentation of skeletal muscle PGC1α expression following acute exercise. However, this effect does not appear to be related to an effect of MitoQ supplementation on HIIT-induced mitochondrial biogenesis in skeletal muscle and may therefore be the result of other adaptations mediated by PGC1α.

Methylglyoxal reduces molecular responsiveness to 4 weeks of endurance exercise in mouse plantaris muscle

2022 ◽  
Author(s):  
Tatsuro Egawa ◽  
Takeshi Ogawa ◽  
Takumi Yokokawa ◽  
Kohei Kido ◽  
Katsumasa Goto ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endurance Exercise ◽  
Mitochondrial Biogenesis ◽  
Insulin Signaling ◽  
Exercise Group ◽  
Voluntary Exercise ◽  
Plantaris Muscle ◽  
Muscle Adaptations ◽  
Exercise Induced ◽  
Skeletal Muscle Adaptations

Endurance exercise triggers skeletal muscle adaptations, including enhanced insulin signaling, glucose metabolism, and mitochondrial biogenesis. However, exercise-induced skeletal muscle adaptations may not occur in some cases, a condition known as exercise-resistance. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite and has detrimental effects on the body such as causing diabetic complications, mitochondrial dysfunction, and inflammation. This study aimed to clarify the effect of methylglyoxal on skeletal muscle molecular adaptations following endurance exercise. Mice were randomly divided into 4 groups (n = 12 per group): sedentary control group, voluntary exercise group, MG-treated group, and MG-treated with voluntary exercise group. Mice in the voluntary exercise group were housed in a cage with a running wheel, while mice in the MG-treated groups received drinking water containing 1% MG. Four weeks of voluntary exercise induced several molecular adaptations in the plantaris muscle, including increased expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), mitochondria complex proteins, toll-like receptor 4 (TLR4), 72-kDa heat shock protein (HSP72), hexokinase II, and glyoxalase 1; this also enhanced insulin-stimulated Akt Ser473 phosphorylation and citrate synthase activity. However, these adaptations were suppressed with MG treatment. In the soleus muscle, the exercise-induced increases in the expression of TLR4, HSP72, and advanced glycation end products receptor 1 were inhibited with MG treatment. These findings suggest that MG is a factor that inhibits endurance exercise-induced molecular responses including mitochondrial adaptations, insulin signaling activation, and the upregulation of several proteins related to mitochondrial biogenesis, glucose handling, and glycation in primarily fast-twitch skeletal muscle.

scholarly journals Adult skeletal muscle deletion of Mitofusin 1 and 2 impedes exercise performance and training capacity

2019 ◽  
Vol 126 (2) ◽  
pp. 341-353 ◽  
Author(s):  
Margaret B. Bell ◽  
Zachary Bush ◽  
Graham R. McGinnis ◽  
Glenn C. Rowe
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Exercise Capacity ◽  
Exercise Performance ◽  
Complex I ◽  
Voluntary Exercise ◽  
Complex Activity ◽  
Complex Iv ◽  
Adult Skeletal Muscle ◽  
Subunit Expression

Endurance exercise has been shown to be a positive regulator of skeletal muscle metabolic function. Changes in mitochondrial dynamics (fusion and fission) have been shown to influence mitochondrial oxidative capacity. We therefore tested whether genetic disruption of mitofusins (Mfns) affected exercise performance in adult skeletal muscle. We generated adult-inducible skeletal muscle-specific Mfn1 (iMS-Mfn1KO), Mfn2 (iMS-Mfn2KO), and Mfn1/2 (iMS-MfnDKO) knockout mice. We assessed exercise capacity by performing a treadmill time to exhaustion stress test before deletion and up to 8 wk after deletion. Analysis of either the iMS-Mfn1KO or the iMS-Mfn2KO did not reveal an effect on exercise capacity. However, analysis of iMS-MfnDKO animals revealed a progressive reduction in exercise performance. We measured individual electron transport chain (ETC) complex activity and observed a reduction in ETC activity in both the subsarcolemmal and intermyofibrillar mitochondrial fractions specifically for NADH dehydrogenase (complex I) and cytochrome- c oxidase (complex IV), which was associated with a decrease in ETC subunit expression for these complexes. We also tested whether voluntary exercise training would prevent the decrease in exercise capacity observed in iMS-MfnDKO animals ( n = 10/group). However, after 8 wk of training we did not observe any improvement in exercise capacity or ETC subunit parameters in iMS-MfnDKO animals. These data suggest that the decrease in exercise capacity observed in the iMS-MfnDKO animals is in part the result of impaired ETC subunit expression and ETC complex activity. Taken together, these results provide strong evidence that mitochondrial fusion in adult skeletal muscle is important for exercise performance. NEW & NOTEWORTHY This study is the first to utilize an adult-inducible skeletal muscle-specific knockout model for Mitofusin (Mfn)1 and Mfn2 to assess exercise capacity. Our findings reveal a progressive decrease in exercise performance with Mfn1 and Mfn2 deletion. The decrease in exercise capacity was accompanied by impaired oxidative phosphorylation specifically for complex I and complex IV. Furthermore, voluntary exercise training was unable to rescue the impairment, suggesting that normal fusion is essential for exercise-induced mitochondrial adaptations.

scholarly journals Effect of Quercetin Treatment on Mitochondrial Biogenesis and Exercise-Induced AMP-Activated Protein Kinase Activation in Rat Skeletal Muscle

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 729 ◽  
Author(s):  
Keiichi Koshinaka ◽  
Asuka Honda ◽  
Hiroyuki Masuda ◽  
Akiko Sato
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Endurance Exercise ◽  
Mitochondrial Biogenesis ◽  
Exercise Performance ◽  
Term Therapy ◽  
High Dose ◽  
Rat Skeletal Muscle ◽  
Amp Activated Protein Kinase ◽  
Quercetin Treatment

The purpose of this study was to evaluate the effect of chronic quercetin treatment on mitochondrial biogenesis, endurance exercise performance and activation levels of AMP-activated protein kinase (AMPK) in rat skeletal muscle. Rats were assigned to a control or quercetin group and were fed for 7 days. Rats treated with quercetin showed no changes in the protein levels of citrate synthase or cytochrome C oxidase IV or those of sirtuin 1, peroxisome proliferator-activated receptor gamma coactivator-1α or phosphorylated AMPK. After endurance swimming exercise, quercetin-treated rats demonstrated no differences in blood and muscle lactate levels or glycogen utilization speed compared to control rats. These results indicate that quercetin treatment does not stimulate mitochondrial biogenesis in skeletal muscle and does not influence metabolism in a way that might enhance endurance exercise capacity. On the other hand, the AMPK phosphorylation level immediately after exercise was significantly lower in quercetin-treated muscles, suggesting that quercetin treatment might provide a disadvantage to muscle adaptation when administered with exercise training. The molecular results of this study indicate that quercetin treatment may not be advantageous for improving endurance exercise performance, at least after high-dose and short-term therapy.

Exercise-Induced Mitochondrial Biogenesis in Skeletal Muscle

2007 ◽  
pp. 37-60 ◽  
Author(s):  
David A. Hood ◽  
Beatrice Chabi ◽  
Keir Menzies ◽  
Michael O’Leary ◽  
Donald Walkinshaw
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Exercise Induced

Dorsomedial hypothalamic corticotropin-releasing factor mediation of exercise-induced anorexia

2005 ◽  
Vol 288 (6) ◽  
pp. R1800-R1805 ◽  
Author(s):  
Maiko Kawaguchi ◽  
Karen A. Scott ◽  
Timothy H. Moran ◽  
Sheng Bi
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Food Intake ◽  
Mrna Expression ◽  
Critical Role ◽  
Voluntary Exercise ◽  
Running Wheel ◽  
Exercise Induced ◽  
Running Wheels ◽  
Induced Changes

Running wheel access and resulting voluntary exercise alter food intake and reduce body weight. The neural mechanisms underlying these effects are unclear. In this study, we first assessed the effects of 7 days of running wheel access on food intake, body weight, and hypothalamic gene expression. We demonstrate that running wheel access significantly decreases food intake and body weight and results in a significant elevation of CRF mRNA expression in the dorsomedial hypothalamus (DMH) but not the paraventricular nucleus. Seven-day running wheel access also results in elevated arcuate nucleus and DMH neuropeptide Y gene expression. To assess a potential role for elevated DMH CRF activity in the activity-induced changes in food intake and body weight, we compared changes in food intake, body weight, and hypothalamic gene expression in rats receiving intracerebroventricular (ICV) CRF antagonist α-helical CRF or vehicle with or without access to running wheels. During a 4-day period of running wheel access, we found that exercise-induced reductions of food intake and body weight were significantly attenuated by ICV injection of the CRF antagonist. The effect on food intake was specific to a blockade of activity-induced changes in meal size. Central CRF antagonist injection further increased DMH CRF mRNA expression in exercised rats. Together, these data suggest that DMH CRF play a critical role in the anorexia resulting from increased voluntary exercise.

scholarly journals Adult expression of PGC-1α and -1β in skeletal muscle is not required for endurance exercise-induced enhancement of exercise capacity

2016 ◽  
Vol 311 (6) ◽  
pp. E928-E938 ◽  
Author(s):  
Christopher Ballmann ◽  
Yawen Tang ◽  
Zachary Bush ◽  
Glenn C. Rowe
Keyword(s):  
Skeletal Muscle ◽  
Exercise Performance ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Adult Skeletal Muscle ◽  
Training Response ◽  
Exercise Induced ◽  
Transport Complex ◽  
Specific Deletion

Exercise has been shown to be the best intervention in the treatment of many diseases. Many of the benefits of exercise are mediated by adaptions induced in skeletal muscle. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators has emerged as being key mediators of the exercise response and is considered to be essential for many of the adaptions seen in skeletal muscle. However, the contribution of the PGC-1s in skeletal muscle has been evaluated by the use of either whole body or congenital skeletal muscle-specific deletion. In these models, PGC-1s were never present, thereby opening the possibility to developmental compensation. Therefore, we generated an inducible muscle-specific deletion of PGC-1α and -1β (iMyo-PGC-1DKO), in which both PGC-1α and -β can be deleted specifically in adult skeletal muscle. These iMyo-PGC-1DKO animals were used to assess the role of both PGC-1α and -1β in adult skeletal muscle and their contribution to the exercise training response. Untrained iMyo-PGC-1DKO animals exhibited a time-dependent decrease in exercise performance 8 wk postdeletion, similar to what was observed in the congenital muscle-specific PGC-1DKOs. However, after 4 wk of voluntary training, the iMyo-PGC-1DKOs exhibited an increase in exercise performance with a similar adaptive response compared with control animals. This increase was associated with an increase in electron transport complex (ETC) expression and activity in the absence of PGC-1α and -1β expression. Taken together these data suggest that PGC-1α and -1β expression are not required for training-induced exercise performance, highlighting the contribution of PGC-1-independent mechanisms.

scholarly journals Skeletal muscle bioenergetics during all-out exercise: mechanistic insight into the oxygen uptake slow component and neuromuscular fatigue

2017 ◽  
Vol 122 (5) ◽  
pp. 1208-1217 ◽  
Author(s):  
Ryan M. Broxterman ◽  
Gwenael Layec ◽  
Thomas J. Hureau ◽  
Markus Amann ◽  
Russell S. Richardson
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Uptake ◽  
Exercise Performance ◽  
Slow Component ◽  
Force Production ◽  
Atp Synthesis ◽  
Peripheral Fatigue ◽  
Synthesis Rate ◽  
Physiological Mechanisms ◽  
Exercise Induced

Although all-out exercise protocols are commonly used, the physiological mechanisms underlying all-out exercise performance are still unclear, and an in-depth assessment of skeletal muscle bioenergetics is lacking. Therefore, phosphorus magnetic resonance spectroscopy (31P-MRS) was utilized to assess skeletal muscle bioenergetics during a 5-min all-out intermittent isometric knee-extensor protocol in eight healthy men. Metabolic perturbation, adenosine triphosphate (ATP) synthesis rates, ATP cost of contraction, and mitochondrial capacity were determined from intramuscular concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), diprotonated phosphate ([Formula: see text]), and pH. Peripheral fatigue was determined by exercise-induced alterations in potentiated quadriceps twitch force (Qtw) evoked by supramaximal electrical femoral nerve stimulation. The oxidative ATP synthesis rate (ATPOX) attained and then maintained peak values throughout the protocol, despite an ~63% decrease in quadriceps maximal force production. ThusATPOX normalized to force production (ATPOX gain) significantly increased throughout the exercise (1st min: 0.02 ± 0.01, 5th min: 0.04 ± 0.01 mM·min−1·N−1), as did the ATP cost of contraction (1st min: 0.048 ± 0.019, 5th min: 0.052 ± 0.015 mM·min−1·N−1). Additionally, the pre- to postexercise change in Qtw (−52 ± 26%) was significantly correlated with the exercise-induced change in intramuscular pH ( r = 0.75) and [Formula: see text] concentration ( r = 0.77). In conclusion, the all-out exercise protocol utilized in the present study elicited a “slow component-like” increase in intramuscular ATPOX gain as well as a progressive increase in the phosphate cost of contraction. Furthermore, the development of peripheral fatigue was closely related to the perturbation of specific fatigue-inducing intramuscular factors (i.e., pH and [Formula: see text] concentration). NEW & NOTEWORTHY The physiological mechanisms and skeletal muscle bioenergetics underlying all-out exercise performance are unclear. This study revealed an increase in oxidative ATP synthesis rate gain and the ATP cost of contraction during all-out exercise. Furthermore, peripheral fatigue was related to the perturbation in pH and deprotonated phosphate ion. These findings support the concept that the oxygen uptake slow component arises from within active skeletal muscle and that skeletal muscle force generating capacity is linked to the intramuscular metabolic milieu.

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