Identification of myokines associated with the pathological stress response in the mdx mouse model of Duchenne muscular dystrophy

PURPOSE: Skeletal muscle constitutes 30-40% of total body mass and is now considered an endocrine organ, given its secretion of a variety proteins, metabolites, and cytokines. We have previously shown that the absence of dystrophin in skeletal muscle contributes to lethal systemic stress pathology in the mdx mouse model of Duchenne muscular dystrophy through a mechanism that remains to be identified. Here we searched for secreted protein signaling factors, or myokines, released from dystrophin-deficient skeletal muscle that influence the organism-wide integrated stress response. We performed skeletal muscle extracellular fluid extraction and discovery proteomics for wild-type, mdx, and transgenic mdx mice rescued by expression of a dystrophin construct, all analyzed under basal conditions and following brief scruff restraint stress that causes inactivity in mdx mice. MAJOR FINDINGS: Our analysis demonstrated that skeletal muscle dystrophinopathy is associated with increased expression of numerous proteins in both intact mdx skeletal muscle and extracellular fluid compared to healthy mice. Brief scruff restraint revealed protein candidates with differential abundance in mdx extracellular fluid. Specifically, altered follistatin-like 1 protein and adiponectin secretion in response to scruff stress was shown to be dependent on skeletal muscle dystrophinopathy. The diverse signaling roles of follistatin-like 1 in the cardiovascular, musculoskeletal, and nervous system implicate it as a particularly intriguing myokine candidate regulating the mdx stress response. CONCLUSIONS: Our current study informs on the skeletal muscle secretory profile in mdx following a stressful stimulus and provides new leads to elucidate the mechanism by which mdx skeletal muscle orchestrates inter-organ stress signaling.