Skeletal muscle proteolysis in response to short-term unloading in humans

Skeletal muscle atrophy is evident after muscle disuse, unloading, or spaceflight and results from decreased protein content as a consequence of decreased protein synthesis, increased protein breakdown or both. At this time, there are essentially no human data describing proteolysis in skeletal muscle undergoing atrophy on Earth or in space, primarily due to lack of valid and accurate methodology. This particular study aimed at assessing the effects of short-term unloading on the muscle contractile proteolysis rate. Eight men were subjected to 72-h unilateral lower limb suspension (ULLS) and intramuscular interstitial levels of the naturally occurring proteolytic tracer 3-methylhistidine (3MH) were measured by means of microdialysis before and on completion of this intervention. The 3MH concentration following 72-h ULLS (2.01 ± 0.22 nmol/ml) was 44% higher ( P < 0.05) than before ULLS (1.56 ± 0.20 nmol/ml). The present experimental model and the employed method determining 3MH in microdialysates present a promising tool for monitoring skeletal muscle proteolysis or metabolism of specific muscles during conditions resulting in atrophy caused by, e.g., disuse and real or simulated microgravity. This study provides evidence that the atrophic processes are evoked rapidly and within 72 h of unloading and suggests that countermeasures should be employed in the early stages of space missions to offset or prevent muscle loss during the period when the rate of muscle atrophy is the highest.

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Effect of short-term hindlimb immobilization on skeletal muscle atrophy and the transcriptome in a low compared with high responder to endurance training model

PLoS ONE ◽

10.1371/journal.pone.0261723 ◽

2022 ◽

Vol 17 (1) ◽

pp. e0261723

Author(s):

Jamie-Lee M. Thompson ◽

Daniel W. D. West ◽

Thomas M. Doering ◽

Boris P. Budiono ◽

Sarah J. Lessard ◽

...

Keyword(s):

Skeletal Muscle ◽

Endurance Training ◽

Muscle Atrophy ◽

Female Rats ◽

Skeletal Muscle Atrophy ◽

Biological Processes ◽

Short Term ◽

Cast Immobilization ◽

Protein Ubiquitination ◽

Differential Gene

Skeletal muscle atrophy is a physiological response to disuse, aging, and disease. We compared changes in muscle mass and the transcriptome profile after short-term immobilization in a divergent model of high and low responders to endurance training to identify biological processes associated with the early atrophy response. Female rats selectively bred for high response to endurance training (HRT) and low response to endurance training (LRT; n = 6/group; generation 19) underwent 3 day hindlimb cast immobilization to compare atrophy of plantaris and soleus muscles with line-matched controls (n = 6/group). RNA sequencing was utilized to identify Gene Ontology Biological Processes with differential gene set enrichment. Aerobic training performed prior to the intervention showed HRT improved running distance (+60.6 ± 29.6%), while LRT were unchanged (-0.3 ± 13.3%). Soleus atrophy was greater in LRT vs. HRT (-9.0 ±8.8 vs. 6.2 ±8.2%; P<0.05) and there was a similar trend in plantaris (-16.4 ±5.6% vs. -8.5 ±7.4%; P = 0.064). A total of 140 and 118 biological processes were differentially enriched in plantaris and soleus muscles, respectively. Soleus muscle exhibited divergent LRT and HRT responses in processes including autophagy and immune response. In plantaris, processes associated with protein ubiquitination, as well as the atrogenes (Trim63 and Fbxo32), were more positively enriched in LRT. Overall, LRT demonstrate exacerbated atrophy compared to HRT, associated with differential gene enrichments of biological processes. This indicates that genetic factors that result in divergent adaptations to endurance exercise, may also regulate biological processes associated with short-term muscle unloading.

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Exercise preconditioning diminishes skeletal muscle atrophy after hindlimb suspension in mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.00137.2018 ◽

2018 ◽

Vol 125 (4) ◽

pp. 999-1010 ◽

Cited By ~ 7

Author(s):

Nicholas T. Theilen ◽

Nevena Jeremic ◽

Gregory J. Weber ◽

Suresh C. Tyagi

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Muscle Atrophy ◽

Mitochondrial Biogenesis ◽

Weight Ratio ◽

Hindlimb Suspension ◽

Skeletal Muscle Atrophy ◽

Short Term ◽

Concurrent Exercise ◽

And Function

The aim of the present study was to investigate whether short-term, concurrent exercise training before hindlimb suspension (HLS) prevents or diminishes both soleus and gastrocnemius atrophy and to analyze whether changes in mitochondrial molecular markers were associated. Male C57BL/6 mice were assigned to control at 13 ± 1 wk of age, 7-day HLS at 12 ± 1 wk of age (HLS), 2 wk of exercise training before 7-day HLS at 10 ± 1 wk of age (Ex+HLS), and 2 wk of exercise training at 11 ± 1 wk of age (Ex) groups. HLS resulted in a 27.1% and 21.5% decrease in soleus and gastrocnemius muscle weight-to-body weight ratio, respectively. Exercise training before HLS resulted in a 5.6% and 8.1% decrease in soleus and gastrocnemius weight-to-body weight ratio, respectively. Exercise increased mitochondrial biogenesis- and function-associated markers and slow myosin heavy chain (SMHC) expression, and reduced fiber-type transitioning marker myosin heavy chain 4 (Myh4). Ex+HLS revealed decreased reactive oxygen species (ROS) and oxidative stress compared with HLS. Our data indicated the time before an atrophic setting, particularly caused by muscle unloading, may be a useful period to intervene short-term, progressive exercise training to prevent skeletal muscle atrophy and is associated with mitochondrial biogenesis, function, and redox balance. NEW & NOTEWORTHY Mitochondrial dysfunction is associated with disuse-induced skeletal muscle atrophy, whereas exercise is known to increase mitochondrial biogenesis and function. Here we provide evidence of short-term concurrent exercise training before an atrophic event protecting skeletal muscle from atrophy in two separate muscles with different, dominant fiber-types, and we reveal an association with the adaptive changes of mitochondrial molecular markers to exercise.

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Skeletal muscle atrophy during short-term disuse: Implications for age-related sarcopenia

Ageing Research Reviews ◽

10.1016/j.arr.2013.07.003 ◽

2013 ◽

Vol 12 (4) ◽

pp. 898-906 ◽

Cited By ~ 158

Author(s):

Benjamin T. Wall ◽

Marlou L. Dirks ◽

Luc J.C. van Loon

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Skeletal Muscle Atrophy ◽

Short Term ◽

Age Related

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Effects of Nandrolone in the Counteraction of Skeletal Muscle Atrophy in a Mouse Model of Muscle Disuse: Molecular Biology and Functional Evaluation

PLoS ONE ◽

10.1371/journal.pone.0129686 ◽

2015 ◽

Vol 10 (6) ◽

pp. e0129686 ◽

Cited By ~ 11

Author(s):

Giulia Maria Camerino ◽

Jean-François Desaphy ◽

Michela De Bellis ◽

Roberta Francesca Capogrosso ◽

Anna Cozzoli ◽

...

Keyword(s):

Skeletal Muscle ◽

Molecular Biology ◽

Mouse Model ◽

Muscle Atrophy ◽

Skeletal Muscle Atrophy ◽

Functional Evaluation ◽

Muscle Disuse

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Faculty Opinions recommendation of Epac2a-knockout mice are resistant to dexamethasone-induced skeletal muscle atrophy and short-term cold stress.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735968750.793561309 ◽

2019 ◽

Author(s):

E Ronald de Kloet ◽

Lisa Koorneef ◽

Onno Meijer

Keyword(s):

Skeletal Muscle ◽

Cold Stress ◽

Muscle Atrophy ◽

Knockout Mice ◽

Skeletal Muscle Atrophy ◽

Short Term

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Dynamics of Toll-like receptors signaling in skeletal muscle atrophy

Current Medicinal Chemistry ◽

10.2174/0929867328666210202113734 ◽

2021 ◽

Vol 28 ◽

Author(s):

Aarti Yadav ◽

Anil Dahuja ◽

Rajesh Dabur

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Inflammatory Cytokine ◽

Muscle Growth ◽

Skeletal Muscle Atrophy ◽

Muscle Loss ◽

Protein Catabolism ◽

Tlr Signaling ◽

Recent Advancement ◽

And Oxidative Stress

: Skeletal muscle atrophy has been characterizedas a state of uncontrolled inflammation and oxidative stress that escalates the protein catabolism. Recent advancement supportsthat impinging signaling molecules in the muscle fibers controlled throughtoll-like receptors (TLR). Activated TLR signalingpathways have been identified as inhibitors of muscle mass and provoke the settings for muscle atrophy. Among them, mainly TLR2 and TLR4 manifest their presence to exacerbate the release of the pro-inflammatory cytokine to deform the synchronized muscle programming. The present review enlightens the TLR signaling mediated muscle loss and their interplay betweeninflammationand skeletal muscle growth.

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Skeletal Muscle Atrophy in Simulated Microgravity Might Be Triggered by Immune-Related microRNAs

Frontiers in Physiology ◽

10.3389/fphys.2018.01926 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 6

Author(s):

Laura Teodori ◽

Alessandra Costa ◽

Luigi Campanella ◽

Maria C. Albertini

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Simulated Microgravity ◽

Skeletal Muscle Atrophy

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MERG1A Protein Abundance Increases in the Atrophied Skeletal Muscle of Denervated Mice, But Does Not Affect NFκB Activity

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab062 ◽

2021 ◽

Author(s):

Luke B Anderson ◽

Barbara Ravara ◽

Sohaib Hameed ◽

Chase D Latour ◽

Sawyer M Latour ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Gastrocnemius Muscle ◽

Ectopic Expression ◽

Dominant Negative ◽

Skeletal Muscle Atrophy ◽

K Channel ◽

Protein Abundance ◽

Muscle Loss ◽

Ubiquitin Proteasome

Abstract Skeletal muscle atrophy may occur with disease, injury, decreased muscle use, starvation, and normal aging. No reliably effective treatments for atrophy are available, thus research into the mechanisms contributing to muscle loss is essential. The ERG1A K+ channel contributes to muscle loss by increasing ubiquitin proteasome proteolysis (UPP) in the skeletal muscle of both unweighted and cachectic mice. Because the mechanisms which produce atrophy vary based upon the initiating factor, here we investigate atrophy produced by denervation. Using immunohistochemistry and immunoblots, we demonstrate that ERG1A protein abundance increases significantly in the Gastrocnemius muscle of rodents 7 days after both sciatic nerve transection and hind limb unweighting. Further, we reveal that ectopic expression of a Merg1a encoded plasmid in normal mouse Gastrocnemius muscle has no effect on activity of the NFκB transcription factor family, a group of proteins which contribute to muscle atrophy by modulation of the UPP. Further, although NFκB activity increases significantly after denervation, we show that expression of a plasmid encoding a dominant negative Merg1a mutant in Gastrocnemius muscle prior to denervation, has no effect on NFκB activity. Thus, although the ERG1A K+ channel increases UPP, it does not do so through modulation of NFκB transcription factors.

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Immobilization-induced activation of key proteolytic systems in skeletal muscles is prevented by a mitochondria-targeted antioxidant

Journal of Applied Physiology ◽

10.1152/japplphysiol.00471.2013 ◽

2013 ◽

Vol 115 (4) ◽

pp. 529-538 ◽

Cited By ~ 79

Author(s):

Erin E. Talbert ◽

Ashley J. Smuder ◽

Kisuk Min ◽

Oh Sung Kwon ◽

Hazel H. Szeto ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Skeletal Muscles ◽

Mammalian Target Of Rapamycin ◽

Skeletal Muscle Atrophy ◽

Muscle Disuse ◽

Mitochondrial Ros ◽

Disuse Muscle Atrophy ◽

Muscle Fiber Atrophy ◽

First Time

Long periods of skeletal muscle disuse result in muscle fiber atrophy, and mitochondrial production of reactive oxygen species (ROS) appears to be a required signal for the increase in protein degradation that occurs during disuse muscle atrophy. The experiments detailed here demonstrate for the first time in limb muscle that the inactivity-induced increases in E3 ligase expression and autophagy biomarkers result from increases in mitochondrial ROS emission. Treatment of animals with a mitochondrial-targeted antioxidant also prevented the disuse-induced decrease in anabolic signaling (Akt/mammalian target of rapamycin signaling) that is normally associated with prolonged inactivity in skeletal muscles. Additionally, our results confirm previous findings that treatment with a mitochondrial-targeted antioxidant is sufficient to prevent casting-induced skeletal muscle atrophy, mitochondrial dysfunction, and activation of the proteases calpain and caspase-3. Collectively, these data reveal that inactivity-induced increases in mitochondrial ROS emission play a required role in activation of key proteolytic systems and the downregulation of important anabolic signaling molecules in muscle fibers exposed to prolonged inactivity.

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