Endoplasmic reticulum stress induces myostatin precursor protein and NF-kappaB 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 myostatin precursor protein (MstnPP) and myostatin (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-IBM, 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 time that the ER stress significantly increased MstnPP mRNA and protein. The results also suggest that in our system ER stress activates NF-kappaB, and we suggest that MstnPP increase occurred through the ER-stress-activated NF-kappaB. We therefore propose a novel mechanism leading to the Mstn increase in s-IBM. Accordingly, interfering with pathways inducing ER stress, NF-kappaB activation or its action on the MstnPP gene promoter might prevent Mstn increase and provide a new therapeutic approach for s-IBM and, possibly, for muscle atrophy in other neuromuscular diseases.
Nogalska
Anna
A
Department of Neurology, USC Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Avenue, Los Angeles, CA 90017, USA.
Wojcik
Slawomir
S
Engel
W King
WK
McFerrin
Janis
J
Askanas
Valerie
V
D000704:Analysis of Variance; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000648:ultrastructure*; D055435:Myostatin; D016328:NF-kappa B / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013312:Stress, Physiological / Q000139:chemically induced / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology
D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; C525911:MSTN protein, human; D018832:Molecular Chaperones; D055435:Myostatin; D016328:NF-kappa B; D011498:Protein Precursors; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014415:Tunicamycin; D019284:Thapsigargin