Endoplasmic Reticulum Stress Induces Myostatin High Molecular Weight Aggregates and Impairs Mature Myostatin Secretion

Sporadic inclusion body myositis (sIBM) is the most prevalent acquired muscle disorder in the elderly with no defined etiology or effective therapy. Endoplasmic reticulum stress and deposition of myostatin, a secreted negative regulator of muscle growth, have been implicated in disease pathology. The myostatin signaling pathway has emerged as a major target for symptomatic treatment of muscle atrophy. Here, we systematically analyzed the maturation and secretion of myostatin precursor MstnPP and its metabolites in a human muscle cell line. We find that increased MsntPP protein levels induce ER stress. MstnPP metabolites were predominantly retained within the endoplasmic reticulum (ER), also evident in sIBM histology. MstnPP cleavage products formed insoluble high molecular weight aggregates, a process that was aggravated by experimental ER stress. Importantly, ER stress also impaired secretion of mature myostatin. Reduced secretion and aggregation of MstnPP metabolites were not simply caused by overexpression, as both events were also observed in wildtype cells under ER stress. It is tempting to speculate that reduced circulating myostatin growth factor could be one explanation for the poor clinical efficacy of drugs targeting the myostatin pathway in sIBM.