Cellular and molecular mechanisms of skeletal muscle atrophy after spinal cord injury

Abstract

Spinal cord injury leads to a rapid and profound loss of skeletal muscle mass. Muscle atrophy consequently promotes metabolic disturbances and leads to increased risk of type 2 diabetes and cardiovascular disease. Prevention of such consequences requires a deeper understanding of underlying molecular and cellular changes, which promote muscle atrophy. This thesis attempts to elucidate some of the mechanisms responsible for muscle atrophy induced by spinal cord injury; specifically, changes in the abundance of regulators of protein metabolism and enzymes responsible for oxidative stress homeostasis in skeletal muscle. Additionally, we examined the impact of spinal cord injury on the differentiation capacity of satellite cells, measured in vitro. Our results suggest most profound changes in skeletal muscle within the first three months post-injury, including higher reactive oxygen species production, apoptosis, and protein turnover. Conversely, we show retained intrinsic satellite cell differentiation capacity, despite substantial changes within skeletal muscle. Collectively, the studies in this thesis encourage efforts to maintain protein metabolism balance and oxidative stress homeostasis during the early post-spinal cord injury phases, as well as rehabilitative interventions targeting satellite cell activation.