In myotonic dystrophy type 1 (DM1), alternative splicing of ryanodine receptor 1 (RyR1) and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) genes has been reported. These proteins are essential for maintaining intracellular Ca2+ in skeletal muscle. To clarify involvement of endoplasmic reticulum (ER) stress in DM1 muscles, we examined the activation of ER stress-related proteins by immunohistochemistry, western blot analysis and RT-PCR. In four of five DM1 muscle biopsies, except for a muscle biopsy from a patient with the shortest CTG expansion and no myotonia, increased expression of GRP78 and calnexin, and phosphorylation of PERK and eIF-α were revealed in fibers with sarcoplasmic masses and in highly atrophic fibers with pyknotic nuclear clumps. Caspase-3 and -7 were also expressed in these fibers. Increased expression of GRP78 in these DM1 muscles was confirmed by western blot analysis. GRP78 mRNA and spliced isoform of XBP1 mRNA were also increased in DM1 muscle biopsies. Furthermore, we demonstrated increased expression of GRP78 in highly atrophic fibers with pyknotic nuclear clumps in all three muscle biopsies from neurogenic muscular atrophies. However, five muscle biopsies from central core disease presumably with disturbed intracellular Ca2+ homeostasis and a muscle biopsy from paramyotonia congenita with myotonia showed no activation of these proteins. Taken together, ER stress is involved in muscle wasting in DM1. However, it seems to be evoked not only by disrupted intracellular Ca2+ homeostasis.
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