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Published on: June 14, 2024
Inhibiting myostatin signaling partially mitigates structural and functional adaptations to hindlimb suspension in
Andrea M Hanson1, Mary H Young1, Brooke C Harrison2
1Aerospace Engineering Sciences, BioServe Space Technologies, University of Colorado, Boulder, CO, USA.
Abstract:
Novel treatments for muscle wasting are of significant value to patients with disease states that result in muscle weakness, injury recovery after immobilization and bed rest, and for astronauts participating in long-duration spaceflight. We utilized an anti-myostatin peptibody to evaluate how myostatin signaling contributes to muscle loss in hindlimb suspension. Male C57BL/6 mice were left non-suspended (NS) or were hindlimb suspended (HS) for 14 days and treated with a placebo vehicle (P) or anti-myostatin peptibody (D). Hindlimb suspension (HS-P) resulted in rapid and significantly decreased body mass (-5.6% by day 13) with hindlimb skeletal muscle mass losses between -11.2% and -22.5% and treatment with myostatin inhibitor (HS-D) partially attenuated these losses. Myostatin inhibition increased hindlimb strength with no effect on soleus tetanic strength. Soleus mass and fiber CSA were reduced with suspension and did not increase with myostatin inhibition. In contrast, the gastrocnemius showed histological evidence of wasting with suspension that was partially mitigated with myostatin inhibition. While expression of genes related to protein degradation (Atrogin-1 and Murf-1) in the tibialis anterior increased with suspension, these atrogenes were not significantly reduced by myostatin inhibition despite a modest activation of the Akt/mTOR pathway. Taken together, these findings suggest that myostatin is important in hindlimb suspension but also motivates the study of other factors that contribute to disuse muscle wasting. Myostatin inhibition benefitted skeletal muscle size and function, which suggests therapeutic potential for both spaceflight and terrestrial applications.
Insights
Novel treatments targeting myostatin can combat muscle wasting from disuse, such as during spaceflight or recovery from immobilization. This study shows anti-myostatin peptibodies partially protected against muscle loss and maintained strength in mice.
Area of Science:
- Muscle physiology and molecular biology
- Spaceflight research
- Therapeutic interventions for muscle atrophy
Background:
- Muscle wasting (atrophy) is a significant clinical challenge, impacting recovery from immobilization, bed rest, and long-duration spaceflight.
- Myostatin is a key negative regulator of skeletal muscle mass, making it a potential therapeutic target.
Purpose of the Study:
- To investigate the role of myostatin signaling in hindlimb suspension-induced muscle loss.
- To evaluate the efficacy of an anti-myostatin peptibody in mitigating muscle wasting and functional deficits.
Main Methods:
- Hindlimb suspension model in C57BL/6 mice for 14 days.
- Treatment with either a placebo vehicle or an anti-myostatin peptibody.
- Assessment of body mass, skeletal muscle mass, muscle strength, and gene expression related to muscle protein degradation.
Main Results:
- Hindlimb suspension caused significant body and muscle mass loss, which was partially attenuated by anti-myostatin treatment.
- Myostatin inhibition improved hindlimb strength but did not affect soleus muscle strength or size.
- Histological evidence of gastrocnemius wasting was mitigated by myostatin inhibition, while tibialis anterior atrogene expression was not significantly reduced.
Conclusions:
- Myostatin plays a significant role in disuse-induced muscle atrophy during hindlimb suspension.
- Anti-myostatin therapy demonstrates potential for preserving skeletal muscle size and function in both spaceflight and terrestrial applications.
- Further research is warranted to explore other factors contributing to disuse muscle wasting.
