Parkin-Dependent Pathway is differentially regulated in immobilized ratGastronemius and Tibialis anterior muscles

Session 4: Proteolysis in health and diseasesPeriods of immobilization or acute inactivity are associated with weakness and/or frailty, and further contribute to muscle atrophy and elevated healthcare costs. Muscle wasting is often associated with mitochondria (mt) alterations and autophagy is required for muscle mass maintenance through the elimination of defective mitochondria. Tibialis anterior (TA) and gastrocnemius (GA) rat muscles exhibit different mitochondria-associated apoptotic responses to immobilization and recovery (1). We therefore investigated the regulation of mitochondria quality control in the TA and the GA following 8 days of immobilization (I8) and 6 days of remobilization (R6) in rats. The mtDNA / genomic DNA ratio decreased in both muscles at I8 and R6, suggesting a decrease in mitochondria abundance. The levels for the fission protein Fis1 were elevated in the TA at I8 and in both muscles at R6, while levels for the fusion proteins Opa1 and Mfn2 were elevated at R6 only in the TA. Thus, fusion and fission processes were imbalanced during immobilization and remobilization, underwent muscle-specific alterations, and followed a different temporal regulation in the TA and the GA. The Pink-Parkin dependent selective pathway for addressing altered mitochondria to autophagy also showed a muscle-specific regulation. Indeed, only the immobilized and/or remobilized GA exhibited elevated mRNA levels for Pink and Parkin and protein levels for VDAC1. However, P62 protein levels increased during immobilization in both muscles at I8 and remained elevated only in the GA during remobilization. However, although this suggest a selective addressing altered mitochondria to autophagy in both muscles, Rab32 mRNA levels and LC3 lipidation increased only in the TA during immobilization and remobilization. Altogether, we suggest that the addressing altered mitochondria for elimination following immobilization involved different muscle-specific mechanisms that should be further investigated. They may include either a different temporal regulation of the Pink-Parkin dependent pathway in the GA and the TA and/or a muscle specific regulation of the LC3 dependent pathway in the TA and the GA. The latter may imply the formation of mitochondria-derived vesicles in the GA that would be directly driven to late endosomes independently of LC3.Reference (1) Slimani L, Micol D, Amat J, Delcros G, Meunier B, Taillandier D, Polge C, Béchet D, Dardevet D, Picard B, Attaix D, Listrat A, Combaret L. The worsening of tibialis anterior muscle atrophy during recovery post-immobilization correlates with enhanced connective tissue area, proteolysis, and apoptosis. Am J Physiol Endocrinol Metab. 2012, 303, E1335-47