Striated muscle activator of Rho signaling is required for myotube survival but does not influence basal protein synthesis or degradation

Abstract

Skeletal muscle mass is regulated by sensing and transmitting extracellular mechanical stress signals to intracellular signaling pathways controlling protein synthesis and degradation. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein that is sensitive to extracellular stress signals. STARS stimulates actin polymerization and influences serum response factor (SRF) and peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α transcription of genes involved in muscle growth, structure, and contraction. The role of STARS in skeletal muscle cells is not well understood. This study investigated whether STARS influenced C2C12 myotube growth by regulating protein synthesis and degradation. The influence of STARS on Pgc-1α, Srf, and Errα mRNA levels, as well as several of their downstream targets involved in muscle cell growth, contraction, and metabolism, was also investigated. STARS overexpression increased actin polymerization, with no effect on protein synthesis, protein degradation, or Akt phosphorylation. STARS overexpression increased Pgc-1α, Srf, Ckmt2, Cpt-1β, and Mhc1 mRNA. STARS knockdown reduced actin polymerization and increased cell death and dead cell protease activity. It also increased markers of inflammation (Casp1, Il-1β, and Mcp-1), regeneration (Socs3 and Myh8), and fast myosin isoforms (Mhc2a and Mhc2x). We show for the first time in muscle cells that STARS overexpression increases actin polymerization and shifts the muscle cell to a more oxidative phenotype. The suppression of STARS causes cell death and increases markers of necrosis, inflammation, and regeneration. As STARS levels are suppressed in clinical models associated with increased necrosis and inflammation, such as aging and limb immobilization, rescuing STARS maybe a future therapeutic strategy to maintain skeletal muscle function and attenuate contraction-induced muscle damage.