Myostatin is a key mediator between energy metabolism and endurance capacity of skeletal muscle

Myostatin (Mstn) participates in the regulation of skeletal muscle size and has emerged as a regulator of muscle metabolism. Here, we hypothesized that lack of myostatin profoundly depresses oxidative phosphorylation-dependent muscle function. Toward this end, we explored Mstn −/− mice as a model for the constitutive absence of myostatin and AAV-mediated overexpression of myostatin propeptide as a model of myostatin blockade in adult wild-type mice. We show that muscles from Mstn −/− mice, although larger and stronger, fatigue extremely rapidly. Myostatin deficiency shifts muscle from aerobic toward anaerobic energy metabolism, as evidenced by decreased mitochondrial respiration, reduced expression of PPAR transcriptional regulators, increased enolase activity, and exercise-induced lactic acidosis. As a consequence, constitutively reduced myostatin signaling diminishes exercise capacity, while the hypermuscular state of Mstn−/− mice increases oxygen consumption and the energy cost of running. We wondered whether these results are the mere consequence of the congenital fiber-type switch toward a glycolytic phenotype of constitutive Mstn −/− mice. Hence, we overexpressed myostatin propeptide in adult mice, which did not affect fiber-type distribution, while nonetheless causing increased muscle fatigability, diminished exercise capacity, and decreased Pparb/d and Pgc1a expression. In conclusion, our results suggest that myostatin endows skeletal muscle with high oxidative capacity and low fatigability, thus regulating the delicate balance between muscle mass, muscle force, energy metabolism, and endurance capacity.

Download Full-text

Skeletal myofiber VEGF regulates contraction-induced perfusion and exercise capacity but not muscle capillarity in adult mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00533.2015 ◽

2016 ◽

Vol 311 (1) ◽

pp. R192-R199 ◽

Cited By ~ 11

Author(s):

Amy E. Knapp ◽

Daniel Goldberg ◽

Hamid Delavar ◽

Breanna M. Trisko ◽

Kechun Tang ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Contraction ◽

Exercise Capacity ◽

Fatigue Resistance ◽

Gene Deletion ◽

Endurance Capacity ◽

Force Frequency ◽

Vegf Gene ◽

Adult Mice ◽

Skeletal Myofiber

A single bout of exhaustive exercise signals expression of vascular endothelial growth factor (VEGF) in the exercising muscle. Previous studies have reported that mice with life-long deletion of skeletal myofiber VEGF have fewer capillaries and a severe reduction in endurance exercise. However, in adult mice, VEGF gene deletion conditionally targeted to skeletal myofibers limits exercise capacity without evidence of capillary regression. To explain this, we hypothesized that adult skeletal myofiber VEGF acutely regulates skeletal muscle perfusion during muscle contraction. A tamoxifen-inducible skeletal myofiber-specific VEGF gene deletion mouse (skmVEGF−/−) was used to reduce skeletal muscle VEGF protein by 90% in adult mice. Three weeks after inducing deletion of the skeletal myofiber VEGF gene, skmVEGF−/− mice exhibited diminished maximum running speed (−10%, P < 0.05) and endurance capacity (−47%; P < 0.05), which did not persist after 8 wk. In skmVEGF−/− mice, gastrocnemius complex time to fatigue measured in situ was 71% lower than control mice. Contraction-induced perfusion measured by optical imaging during a period of electrically stimulated muscle contraction was 85% lower in skmVEGF−/− than control mice. No evidence of capillary rarefication was detected in the soleus, gastrocnemius, and extensor digitorum longus (EDL) up to 8 wk after tamoxifen-induced VEGF ablation, and contractility and fatigue resistance of the soleus measured ex vivo were also unchanged. The force-frequency of the EDL showed a small right shift, but fatigue resistance did not differ between EDL from control and skmVEGF−/− mice. These data suggest myofiber VEGF is required for regulating perfusion during periods of contraction and may in this manner affect endurance capacity.

Download Full-text

Diaphragm arterioles are less responsive to α1- adrenergic constriction than gastrocnemius arterioles

Journal of Applied Physiology ◽

10.1152/japplphysiol.01152.2001 ◽

2002 ◽

Vol 92 (5) ◽

pp. 1808-1816 ◽

Cited By ~ 49

Author(s):

Aaron Aaker ◽

M. H. Laughlin

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Gastrocnemius Muscle ◽

Fiber Type ◽

Muscle Blood Flow ◽

Oxidative Capacity ◽

Receptor Stimulation ◽

Exercise Induced ◽

Fast Twitch

The sympathetic nervous system has greater influence on vascular resistance in low-oxidative, fast-twitch skeletal muscle than in high-oxidative skeletal muscle (17). The purpose of this study was to test the hypothesis that arterioles isolated from low-oxidative, fast-twitch skeletal muscle [the white portion of gastrocnemius (WG)] possess greater responsiveness to adrenergic constriction than arterioles isolated from high-oxidative skeletal muscle [red portion of the gastrocnemius muscle (RG) and diaphragm (Dia)]. Second-order arterioles (2As) were isolated from WG, RG, and Dia of rats and reactivity examined in vitro. Results reveal that Dia 2As constrict less to norepinephrine (NE) (10−9 to 10 −4 M) than 2As from RG and WG, which exhibited similar NE-induced constrictions. This difference was not endothelium dependent, because responses of denuded 2As were similar to those of intact arterioles. The blunted NE-induced constrictor response of Dia 2As appears to be the result of differences in α1-receptor effects because 1) arterioles from Dia also responded less to selective α1-receptor stimulation with phenylephrine than RG and WG arterioles; 2) arterioles from Dia, RG, and WG dilated similarly to isoproterenol (10−9 to 10−4 M) and did not respond to selective α2-receptor stimulation with UK-14304; and 3) endothelin-1 produced similar constriction in 2As from Dia, RG, and WG. We conclude that differences in oxidative capacity and/or fiber type composition of muscle tissue do not explain different NE responsiveness of Dia 2As compared with 2As from gastrocnemius muscle. Differences in α1-adrenergic constrictor responsiveness among arterioles in skeletal muscle may contribute to nonuniform muscle blood flow responses observed during exercise and serve to maintain blood flow to Dia during exercise-induced increases in sympathetic nerve activity.

Download Full-text

Overcoming nature’s paradox in skeletal muscle to optimise animal production

Animal Production Science ◽

10.1071/an19361 ◽

2019 ◽

Vol 59 (11) ◽

pp. 1957

Author(s):

Gordon S. Lynch ◽

René Koopman

Keyword(s):

Skeletal Muscle ◽

Muscle Fibre ◽

Oxidative Capacity ◽

Animal Production ◽

Food Sources ◽

Muscle Size ◽

Meat Production ◽

Endurance Capacity ◽

Muscle Fibre Size ◽

Fibre Size

Nature’s paradox in skeletal muscle describes the seemingly mutually exclusive relationship between muscle fibre size and oxidative capacity. In mammals, there is a constraint on the size at which mitochondria-rich, high O2-dependent oxidative fibres can attain before they become anoxic or adapt to a glycolytic phenotype, being less reliant on O2. This implies that a muscle fibre can hypertrophy at the expense of its endurance capacity. Adaptations to activity (exercise) generally obey this relationship, with optimal muscle endurance generally being linked to an enhanced proportion of small, slow oxidative fibres and muscle strength (force and/or power) being linked to an enhanced proportion of large, fast glycolytic fibres. This relationship generally constrains not only the physiological limits of performance (e.g. speed and endurance), but also the capacity to manipulate muscle attributes such as fibre size and composition, with important relevance to the livestock and aquaculture industries for producing specific muscle traits such as (flesh) quality, texture and taste. Highly glycolytic (white) muscles have different traits than do highly oxidative (red) muscles and so the ability to manipulate muscle attributes to produce flesh with specific traits has important implications for optimising meat production and quality. Understanding the biological regulation of muscle size, and phenotype and the capacity to manipulate signalling pathways to produce specific attributes, has important implications for promoting ethically sustainable and profitable commercial livestock and aquaculture practices and for developing alternative food sources, including ‘laboratory meat’ or ‘clean meat’. This review describes the exciting potential of manipulating muscle attributes relevant to animal production, through traditional nutritional and pharmacological approaches and through viral-mediated strategies that could theoretically push the limits of muscle fibre growth, adaptation and plasticity.

Download Full-text

The KATP channel Kir6.2 subunit content is higher in glycolytic than oxidative skeletal muscle fibers

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00663.2010 ◽

2011 ◽

Vol 301 (4) ◽

pp. R916-R925 ◽

Cited By ~ 18

Author(s):

Krystyna Banas ◽

Charlene Clow ◽

Bernard J. Jasmin ◽

Jean-Marc Renaud

Keyword(s):

Skeletal Muscle ◽

Cross Sections ◽

Fiber Type ◽

Energy Levels ◽

Muscle Fibers ◽

Metabolic Stress ◽

Oxidative Capacity ◽

Fiber Types ◽

Fiber Damage ◽

The Individual

It has long been suggested that in skeletal muscle, the ATP-sensitive K+ channel (KATP) channel is important in protecting energy levels and that abolishing its activity causes fiber damage and severely impairs function. The responses to a lack of KATP channel activity vary between muscles and fibers, with the severity of the impairment being the highest in the most glycolytic muscle fibers. Furthermore, glycolytic muscle fibers are also expected to face metabolic stress more often than oxidative ones. The objective of this study was to determine whether the t-tubular KATP channel content differs between muscles and fiber types. KATP channel content was estimated using a semiquantitative immunofluorescence approach by staining cross sections from soleus, extensor digitorum longus (EDL), and flexor digitorum brevis (FDB) muscles with anti-Kir6.2 antibody. Fiber types were determined using serial cross sections stained with specific antimyosin I, IIA, IIB, and IIX antibodies. Changes in Kir6.2 content were compared with changes in CaV1.1 content, as this Ca2+ channel is responsible for triggering Ca2+ release from sarcoplasmic reticulum. The Kir6.2 content was the lowest in the oxidative soleus and the highest in the glycolytic EDL and FDB. At the individual fiber level, the Kir6.2 content within a muscle was in the order of type IIB > IIX > IIA ≥ I. Interestingly, the Kir6.2 content for a given fiber type was significantly different between soleus, EDL, and FDB, and highest in FDB. Correlations of relative fluorescence intensities from the Kir6.2 and CaV1.1 antibodies were significant for all three muscles. However, the variability in content between the three muscles or individual fibers was much greater for Kir6.2 than for CaV1.1. It is suggested that the t-tubular KATP channel content increases as the glycolytic capacity increases and as the oxidative capacity decreases and that the expression of KATP channels may be linked to how often muscles/fibers face metabolic stress.

Download Full-text

MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis

Nature Communications ◽

10.1038/s41467-020-20790-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Joseph C. Reynolds ◽

Rochelle W. Lai ◽

Jonathan S. T. Woodhead ◽

James H. Joly ◽

Cameron J. Mitchell ◽

...

Keyword(s):

Skeletal Muscle ◽

Healthy Aging ◽

Metabolic Stress ◽

Muscle Metabolism ◽

Physical Capacity ◽

Physical Decline ◽

Age Dependent ◽

Exercise Induced ◽

Muscle Homeostasis ◽

Metabolic Fitness

AbstractHealthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes.

Download Full-text

Skeletal muscle beta-adrenergic receptors: variations due to fiber type and training

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1984.246.2.e160 ◽

1984 ◽

Vol 246 (2) ◽

pp. E160-E167 ◽

Cited By ~ 23

Author(s):

R. S. Williams ◽

M. G. Caron ◽

K. Daniel

Keyword(s):

Skeletal Muscle ◽

Adrenergic Receptors ◽

Fiber Type ◽

Succinic Dehydrogenase ◽

Oxidative Capacity ◽

Treadmill Running ◽

Beta Adrenergic Receptors ◽

Control Groups ◽

Beta Adrenergic ◽

Physiological Importance

To determine the relationship between oxidative capacity and characteristics of beta-adrenergic receptors (beta AR) in skeletal muscle, selected biochemical variables were quantitated in particulate preparations from soleus and gastrocnemius muscle from rats subjected to 10 wk of treadmill running and from three control groups: free-fed, sedentary controls; food-restricted, pair-weighted controls; and animals trained by swimming. Beta AR density and isoproterenol-stimulated adenylate cyclase activity were considerably greater in the slow-twitch oxidative soleus muscle than in the mixed fiber type gastrocnemius in animals from each group (P less than 0.005). Succinic dehydrogenase (SDH) activity of gastrocnemius was increased 23-42% (P less than 0.05) in runners over each of the control groups, concommitantly with a 15-27% increase (P less than 0.05) in beta AR density (Bmax for binding of 125I-cyanopindolol). In 24 animals from all four treatment groups, there was a significant correlation between SDH activity and beta AR density (r = 0.68; P less than 0.001). We conclude that BAR density correlates positively with oxidative capacity in skeletal muscle, but further studies are required to determine the physiological importance of these differences.

Download Full-text

Blood flow to different skeletal muscle fiber types during contraction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1983.245.2.h265 ◽

1983 ◽

Vol 245 (2) ◽

pp. H265-H275 ◽

Cited By ~ 30

Author(s):

B. G. Mackie ◽

R. L. Terjung

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Muscle Fiber ◽

Fiber Type ◽

Oxidative Capacity ◽

Skeletal Muscle Fiber ◽

Muscle Fiber Types ◽

Fiber Types ◽

Blood Flows ◽

Fast Twitch

Blood flow to fast-twitch red (FTR), fast-twitch white (FTW), and slow-twitch red (STR) muscle fiber sections of the gastrocnemius-plantaris-soleus muscle group was determined using 15 +/- 3-microns microspheres during in situ stimulation in pentobarbital-anesthetized rats. Steady-state blood flows were assessed during the 10th min of contraction using twitch (0.1, 0.5, 1, 3, and 5 Hz) and tetanic (7.5, 15, 30, 60, and 120/min) stimulation conditions. In addition, an earlier blood flow determination was begun at 3 min (twitch series) or at 30 s (tetanic series) of stimulation. Blood flow was highest in the FTR (220-240 ml X min-1 X 100 g-1), intermediate in the STR (140), and lowest in the FTW (70-80) section during tetanic contraction conditions estimated to coincide with the peak aerobic function of each fiber type. These blood flows are fairly proportional to the differences in oxidative capacity among fiber types. Further, their absolute values are similar to those predicted from the relationship between blood flow and oxidative capacity found by others for dog and cat muscles. During low-frequency contraction conditions, initial blood flow to the FTR and STR sections were excessively high and not dependent on contraction frequency. However, blood flows subsequently decreased to values in keeping with the relative energy demands. In contrast, FTW muscle did not exhibit this time-dependent relative hyperemia. Thus, besides the obvious quantitative differences between skeletal muscle fiber types, there are qualitative differences in blood flow response during contractions. Our findings establish that, based on fiber type composition, a heterogeneity in blood flow distribution can occur within a whole muscle during contraction.

Download Full-text

Association between vitamin D deficiency and exercise capacity in patients with CKD, a cross-sectional analysis

10.1101/2020.10.26.350546 ◽

2020 ◽

Author(s):

Emma L Watson ◽

Thomas J Wilkinson ◽

Tom F O’Sullivan ◽

Luke A Baker ◽

Douglas W Gould ◽

...

Keyword(s):

Skeletal Muscle ◽

Vitamin D ◽

Vitamin D Deficiency ◽

Exercise Capacity ◽

Muscle Mass ◽

Ex Vivo ◽

Muscle Size ◽

Cross Sectional ◽

Cross Sectional Analysis ◽

Sectional Analysis

AbstractEvidence is growing for a role of vitamin D in regulating skeletal muscle mass, strength and functional capacity. Given the role the kidneys play in activating total vitamin D, and the high prevalence of vitamin D deficiency in Chronic Kidney Disease (CKD), it is possible that deficiency contributes to the low levels of physical function and muscle mass in these patients. This is a secondary cross-sectional analysis of previously published interventional study, with ex vivo follow up work. 34 CKD patients at stages G3b-5 (eGFR 25.5 ± 8.3ml/min/1.73m2; age 61 ± 12 years) were recruited, with a sub-group (n=20) also donating a muscle biopsy. Vitamin D and associated metabolites were analysed in plasma by liquid chromatography tandem-mass spectroscopy and correlated to a range of physiological tests of muscle size, function, exercise capacity and body composition. The effects of 1α,25(OH)2D3 supplementation on myogenesis and myotube size was investigated in primary skeletal muscle cells from vitamin D deficient donors. In vivo, there was no association between total or active vitamin D and muscle size or strength, but a significant correlation with was seen with the total form. Ex vivo, 1α,25(OH)2D3 supplementation reduced IL-6 mRNA expression, but had no effect upon proliferation, differentiation or myotube diameter. This early preliminary work suggests that vitamin D deficiency is not a prominent factor driving the loss of muscle mass in CKD, but may play a role in reduced exercise capacity.

Download Full-text