Skeletal muscle apoptosis following 7 days of denervation‐induced muscle disuse

Abstract

Chronic decreases in skeletal muscle contractile activity result in muscle atrophy, reduced force production and increased fatigue. However, the mechanisms of disuse‐induced activation of apoptotic signaling cascades which lead to atrophy are not fully established. To study these pathways C57BL/6 (WT) and Bax/Bak knockout (KO) animals were denervated for 7 days. This model of muscle disuse resulted in a decrease in mitochondrial respiration and a 2‐fold increase in the production of reactive oxygen species. Activity of the anti‐oxidant enzyme catalase was elevated by 2.5‐fold in subsarcolemmal (SS) mitochondria from WT and KO animals. Denervation resulted in higher cofilin levels within SS mitochondria, suggesting an increased rate of cofilin translocation from the cytosol. This translocation of cofilin may have contributed to the approximate 2‐fold increase in cleaved Poly‐ADP ribose polymerase (Parp) following disuse. Denervation also resulted in a 1.7‐fold increase in DNA fragmentation in WT animals, but no fragmentation was evident in the KO group. These data suggest that: 1) Bax and Bak contribute to the degree of DNA fragmentation following denervation and 2) chronic muscle disuse increases oxidative stress which stimulates the translocation of pro‐apoptotic proteins, such as cofilin, to promote protein release, and contribute to the loss of muscle mass. This work was supported by NSERC.