Mechanisms of skeletal muscle fatigue following eccentric contractions <Summaries of the Doctoral Theses>

It is well-known that eccentric contractions (Ecc), in which muscles are stretched while contracting, result in immediate and prolonged force depressions. However, the mechanisms underlying this type of fatigue were not fully understood. The present study tested the hypothesis that long-lasting muscle fatigue following Ecc would be attributable to the functional deficit in sarcoplasmic reticulum (SR) and myofibril through the protein degradation by the calpain pathway. To this end, rat extensor digitorum longus and tibialis anterior muscles were exposed to 200-repeated contractions and used for measures of force output and for biochemical analyses, respectively. The experiment 1 showed that the SR Ca2+ release and uptake rate, the myofbrillar ATPase activity and the relative content of myosin heavy chain were decreased 4-6 days after Ecc, but not immediately after Ecc. These alterations were specific for Ecc and not observed for isometric contractions. These results imply that functional impairment in the SR and myofibril may contribute, at least partly, to Ecc-induced muscle fatigue which can take a number of days to recover. In the experiment 2, several (3-6) days after Ecc, decreases in the SR Ca2+ release and uptake rate were observed to be accompanied by reductions in the protein contents of SR Ca2+ release channel and Ca2+-ATPase, suggesting that disturbances in Ca2+ uptake and release would result from the degradation of corresponding molecules. Skeletal muscle expresses mainly three distinct calpain isoforms, i.e., μ-calpain, m-calpain and calpain-3. The experiment 3 revealed that all three isoforms were autolyzed following Ecc. Calpain-3 was autolyzed earlier than μ-calpain, while μ-calpain was autolyzed earlier than m-calpain. In the experiment 4, specific inhibition of μ-calpain and m-calpain with the infusion of MDL-28170 was found to attenuate a loss of force production and reductions in SR and myofibrillar function 3 days after Ecc. These findings in the present study suggest that long-lasting