Inhibition of Calpain Decreases Muscle Weakness During Unloading

Abstract

Unloading skeletal muscle results in atrophy and a decreased ability of the remaining muscle to generate force. Reduced atrophy has been reported when calpain activity is inhibited during unloading, but the impact on force generating capability has not been established. Our hypothesis is that endogenous inhibition of calpain through muscle specific overexpression of calpastatin prevents the loss of mass and the decreased specific force (N/cm2) observed with unloading. Wild type (wt) and calpastatin overexpressing (cp) mice were subjected to hind limb suspension (HS). Following 3, 9, or 14 days of HS, soleus and extensor digitorum longus (EDL) muscles were removed from anesthetized mice and maximum isometric force (Po) was measured in vitro. Compared with muscles of non‐suspended mice, soleus muscles of wt mice showed a 25% loss in mass after only 3 days of HS that was maintained to day 14 and specific Po demonstrated a progressive decline that reached ~30% by day 14. In cp mice, a decrease in specific Po for soleus muscles was not observed until day 14, when the value was only 10% lower than that for muscles of non‐suspended cp mice. EDL muscles were unaffected by HS in either wt or cp mice. We conclude that inhibition of calpain activity by overexpression of calpastatin protects the soleus muscle from atrophy associated with unloading and maintains the integrity of the force generating apparatus. Support from NASA NNCO 4AA21 A.