LaminA/C-dependent cellular senescence signaling promotes skeletal muscle atrophy and abnormalities in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease affecting the central nervous system with effects on the skeletal muscle that entails detailed characterization. Several PD-associated motor symptoms, such as rigidity, movement delays and postural instability, involve the skeletal muscle. We used the human α-syn A53T mutant mouse model to characterize the PD-associated skeletal muscle abnormalities. These mice exhibit reduced muscle weight, myofiber size and grip strength at PD onset. Gain of slow muscle fibers at the expense of fast fibers, muscle stem cell number alterations, elevated fibrosis and neuromuscular junction degeneration were observed in these mice. Oxidative stress and DNA damage-associated pathways led to reduced levels of the nuclear membrane protein LaminA/C, causing accelerated cellular senescence in the A53T muscle. We identify a molecular pathway of senescence-associated secretory phenotype activating FoxO signaling, resulting in skeletal muscle loss in the A53T mice. Thus, increased oxidative stress and accumulated cellular senescence could underlie the PD-associated musculoskeletal defects, with potential therapeutic significance.