Endoplasmic reticulum stress induces myostatin precursor protein and NF-κB in cultured human muscle fibers:: Relevance to inclusion body myositis

sporadic-inclusion body myositis (s-IBM) is the most common progressive muscle disease of older persons. It leads to pronounced muscle fiber atrophy and weakness, and there is no successful treatment. We have previously shown that myostain precursor protein (MstmPP) and myostain (Mstn) dimer are increased in biopsied s-IBM muscle fibers, and proposed that MstnPP/Mstn increase may contribute to muscle fiber atrophy and weakness in s-IBM patients. Mstn is known to be a negative regulator of muscle fiber mass. It is synthesized as MstnPP, which undergoes posttranslational processing in the muscle fiber to produce mature, active Mstn. To explore possible mechanisms involved in Mstn abnormalities in s-1IBM, in the present study we utilized primary cultures of normal human muscle fibers and experimentally modified the intracellular micro-environment to induce endoplasmic-reticulum (ER)-stress, thereby mimicking an important aspect of the s-IBM muscle fiber milieu. ER stress was induced by treating well-differentiated cultured muscle fibers with either tunicamycin or thapsigargin, both well-established ER stress inducers. Our results indicate for the first timethat the ER stress significantly increased MstnPP mRNA and protein. The results also suggest that in our system ER stress activates NF-kappa B, and we suggest that MstnPP increase occured through the ER-stress-activated NF-kappa B. We threfore propose a novel mechanism leading to the Mstn increase in s-IBM. Accordingly, interfering with pathways inducing ER stress, NF-kappa B possibly, for muscle atrophy in other neuromuscular diseases. (c) 2006 Elsevier Inc. All rights reserved.