Role of Parkin in amino acid signaling during skeletal muscle atrophy

Abstract

The process of muscle atrophy is highly orderly and regulated. It is characterized by a reduction of muscle fiber cross sectional area and protein content, reduction of power contraction, increase in fatigability and insulin resistance. Several pathways are considered important for the loss of skeletal muscle mass, such as the ubiquitin-proteasome pathway, reactive oxygen species (ROS), autophagy and more recently mitochondrial fission. We have previously shown that leucine, an essential amino acid, acts as a potent inhibitor of skeletal muscle atrophy, and that this effect is dependent on FoxO3a inhibition. In addition muscle mass preservation, leucine, together with other branched-chain amino acid (BCAA), has been identified as an important inducer of mitochondrial biogenesis in muscle fibers. Since mitochondrial biogenesis and mitophagy have been shown to be critical to skeletal muscle atrophy, understanding the effect of leucine on mitochondrial degradation and biogenesis could identify new anti-atrophic pathways involving mitochondria. The E3 ubiquitin ligase Parkin has been demonstrated to be an important regulator of mitochondrial removal and several groups have shown it is highly expressed in skeletal muscle. However, the role of Parkin in skeletal myofiber atrophy is still unknown. Thus, in this proposal, we will investigate how Parkin-mediated mitophagy and mitochondrial function are regulated by leucine during skeletal muscle atrophy. (AU)