De novo ceramides synthesis is not involved in skeletal muscle atrophy induced by short-term mechanical unloading

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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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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Icaritin requires Phosphatidylinositol 3 kinase (PI3K)/Akt signaling to counteract skeletal muscle atrophy following mechanical unloading

Scientific Reports ◽

10.1038/srep20300 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 19

Author(s):

Zong-Kang ZHANG ◽

Jie LI ◽

Jin LIU ◽

Baosheng GUO ◽

Albert LEUNG ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Akt Signaling ◽

Skeletal Muscle Atrophy ◽

Phosphatidylinositol 3 Kinase ◽

Mechanical Unloading ◽

Phosphatidylinositol 3

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Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity

International Journal of Molecular Sciences ◽

10.3390/ijms22063252 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3252

Author(s):

John M. Lawler ◽

Jeffrey M. Hord ◽

Pat Ryan ◽

Dylan Holly ◽

Mariana Janini Gomes ◽

...

Keyword(s):

Skeletal Muscle ◽

Stress Response ◽

Muscle Atrophy ◽

Muscle Fiber ◽

Skeletal Muscle Atrophy ◽

Positive Staining ◽

Angiotensin Ii Receptor ◽

Mechanical Unloading ◽

Muscle Fiber Atrophy ◽

Fiber Atrophy

Insufficient stress response and elevated oxidative stress can contribute to skeletal muscle atrophy during mechanical unloading (e.g., spaceflight and bedrest). Perturbations in heat shock proteins (e.g., HSP70), antioxidant enzymes, and sarcolemmal neuronal nitric oxidase synthase (nNOS) have been linked to unloading-induced atrophy. We recently discovered that the sarcolemmal NADPH oxidase-2 complex (Nox2) is elevated during unloading, downstream of angiotensin II receptor 1, and concomitant with atrophy. Here, we hypothesized that peptidyl inhibition of Nox2 would attenuate disruption of HSP70, MnSOD, and sarcolemmal nNOS during unloading, and thus muscle fiber atrophy. F344 rats were divided into control (CON), hindlimb unloaded (HU), and hindlimb unloaded +7.5 mg/kg/day gp91ds-tat (HUG) groups. Unloading-induced elevation of the Nox2 subunit p67phox-positive staining was mitigated by gp91ds-tat. HSP70 protein abundance was significantly lower in HU muscles, but not HUG. MnSOD decreased with unloading; however, MnSOD was not rescued by gp91ds-tat. In contrast, Nox2 inhibition protected against unloading suppression of the antioxidant transcription factor Nrf2. nNOS bioactivity was reduced by HU, an effect abrogated by Nox2 inhibition. Unloading-induced soleus fiber atrophy was significantly attenuated by gp91ds-tat. These data establish a causal role for Nox2 in unloading-induced muscle atrophy, linked to preservation of HSP70, Nrf2, and sarcolemmal nNOS.

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Thyroid Hormone Protects from Fasting-Induced Skeletal Muscle Atrophy by Promoting Metabolic Adaptation

International Journal of Molecular Sciences ◽

10.3390/ijms20225754 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5754 ◽

Cited By ~ 1

Author(s):

Ucci ◽

Renzini ◽

Russi ◽

Mangialardo ◽

Cammarata ◽

...

Keyword(s):

Skeletal Muscle ◽

Thyroid Hormone ◽

Muscle Atrophy ◽

De Novo ◽

Skeletal Muscle Atrophy ◽

Metabolic Adaptation ◽

Cell Proliferation And Differentiation ◽

Wide Range ◽

Ubiquitin Proteasome ◽

Muscle Homeostasis

Thyroid hormones regulate a wide range of cellular responses, via non-genomic and genomic actions, depending on cell-specific thyroid hormone transporters, co-repressors, or co-activators. Skeletal muscle has been identified as a direct target of thyroid hormone T3, where it regulates stem cell proliferation and differentiation, as well as myofiber metabolism. However, the effects of T3 in muscle-wasting conditions have not been yet addressed. Being T3 primarily responsible for the regulation of metabolism, we challenged mice with fasting and found that T3 counteracted starvation-induced muscle atrophy. Interestingly, T3 did not prevent the activation of the main catabolic pathways, i.e., the ubiquitin-proteasome or the autophagy-lysosomal systems, nor did it stimulate de novo muscle synthesis in starved muscles. Transcriptome analyses revealed that T3 mainly affected the metabolic processes in starved muscle. Further analyses of myofiber metabolism revealed that T3 prevented the starvation-mediated metabolic shift, thus preserving skeletal muscle mass. Our study elucidated new T3 functions in regulating skeletal muscle homeostasis and metabolism in pathological conditions, opening to new potential therapeutic approaches for the treatment of skeletal muscle atrophy.

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Long Noncoding RNA lncMUMA Reverses Established Skeletal Muscle Atrophy following Mechanical Unloading

Molecular Therapy ◽

10.1016/j.ymthe.2018.09.014 ◽

2018 ◽

Vol 26 (11) ◽

pp. 2669-2680 ◽

Cited By ~ 15

Author(s):

Zong-Kang Zhang ◽

Jie Li ◽

Daogang Guan ◽

Chao Liang ◽

Zhenjian Zhuo ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Skeletal Muscle Atrophy ◽

Mechanical Unloading

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The effect of icaritin on skeletal muscle atrophy following mechanical unloading

Planta Medica ◽

10.1055/s-0034-1382591 ◽

2014 ◽

Vol 80 (10) ◽

Author(s):

Z Zhang ◽

WN Leung ◽

G Zhang ◽

J Li ◽

BT Zhang

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Skeletal Muscle Atrophy ◽

Mechanical Unloading

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.90558.2008 ◽

2008 ◽

Vol 105 (3) ◽

pp. 902-906 ◽

Cited By ~ 81

Author(s):

Per A. Tesch ◽

Ferdinand von Walden ◽

Thomas Gustafsson ◽

Richard M. Linnehan ◽

Todd A. Trappe

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Simulated Microgravity ◽

Skeletal Muscle Atrophy ◽

Muscle Loss ◽

Short Term ◽

Promising Tool ◽

Muscle Disuse ◽

Naturally Occurring ◽

Muscle Contractile

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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