title: Endoplasmic reticulum stress response in P104L mutant caveolin-3 transgenic mice.
abstract: Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C). However, the precise molecular pathogenesis of caveolin-3-related muscular dystrophy remains uncertain. Here, we demonstrate the effect of gene dosage on the severity of the myopathic phenotype in P104L mutant caveolin-3 (mCav3(P104L)) transgenic mice, a model of LGMD1C. We analyzed the endoplasmic reticulum (ER) stress response in the transgenic mice and found upregulated transcription of the molecular chaperone, glucose-regulated protein (GRP78). Moreover, signaling downstream of GRP78 in the myofibers was activated toward apoptosis. However, terminal transferase dUTP nick end labeling assays detected a few apoptotic nuclei in transgenic mouse skeletal muscle, probably due to the transcriptional activation of Dad1, an anti-apoptotic factor in the ER. These findings suggest that the ER stress response caused by mCav3(P104L) plays a role in the pathogenesis of LGMD1C as a toxic gain of function effect.
authors: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Kobe, Hyogo 650-0017, Japan.
authors: Atsushi
authors: A
authors: Kuga
authors: Yutaka
authors: Y
authors: Ohsawa
authors: Tadashi
authors: T
authors: Okada
authors: Fumio
authors: F
authors: Kanda
authors: Motoi
authors: M
authors: Kanagawa
authors: Tatsushi
authors: T
authors: Toda
authors: Yoshihide
authors: Y
authors: Sunada