Ryanodine receptor stabilizer S-107 rescues slow-type rat soleus muscle function after 7-day hindlimb unloading

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Abstract
During periods of muscle disuse, calcium accumulates in the myoplasm of slow-tonic muscle fibers, leading to multiple negative consequences for muscle function. Leaky ryanodine receptors (RyRs) could contribute to this excessive accumulation of calcium. We hypothesized that the administration of S-107, a stabilizer of RyRs, would reduce the accumulation of calcium in the myoplasm/mitochondria and improve rat soleus muscle function during disuse. Male Wistar rats underwent 7 days of hindlimb suspension (HS), receiving S-107 in their food daily throughout the experiment. Seven days of HS led to cytosolic and mitochondrial calcium accumulation, enhanced mitochondrial respiration, and reduced mitochondrial biogenesis in the soleus muscle. This was accompanied by reductions in the proportion of slow-type myofibres, maximal isometric force, and fatigue resistance. Administering S-107 during HS prevented the accumulation of calcium in the mitochondria and the overactivation of mitochondrial respiration. It also attenuated the decline in markers of mitochondrial biogenesis and the decrease in fatigue resistance. S-107 treatment also partially prevented the decline in the soleus muscle force production but had only a minor effect on myoplasmic calcium accumulation. Our findings suggest that the destabilization of RyRs during muscle disuse leads to an accumulation of calcium in both the mitochondria and the myoplasm, which in turn causes a decline in muscle strength and resistance to fatigue.
Funding Information
  • Russian Science Foundation (# 23-75-10048, # 23-75-10048, # 23-75-10048, # 23-75-10048, # 23-75-10048, # 23-75-10048, # 23-75-10048)

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