絞り込み

16738

広告

Inositol Trisphosphate Receptor Mediated Ca2+ Signalling Stimulates Mitochondrial Function and Gene Expression in Core Myopathy Patients.

著者 Suman M , Sharpe JA , Bentham RB , Kotiadis VN , Menegollo M , Pignataro V , Molgó J , Muntoni F , Duchen MR , Pegoraro E , Szabadkai G
Hum Mol Genet.2018 Apr 25 ; ():.
この記事をPubMed上で見るPubMedで表示
この記事をGoogle翻訳上で見る Google翻訳で開く

スターを付ける スターを付ける     (6view , 0users)

Full Text Sources

Medical

Miscellaneous

Molecular Biology Databases

Core myopathies are a group of childhood muscle disorders caused by mutations of the ryanodine receptor (RyR1), the Ca2+ release channel of the sarcoplasmic reticulum. These mutations have previously been associated with elevated inositol trisphosphate receptor (IP3R) levels in skeletal muscle myotubes derived from patients. However, the functional relevance and the relationship of IP3R mediated Ca2+ signalling with the pathophysiology of the disease is unclear. It has also been suggested that mitochondrial dysfunction underlies the development of central and diffuse multi-mini-cores, devoid of mitochondrial activity, which is a key pathological consequence of RyR1 mutations. Here we used muscle biopsies of central core and multi-minicore disease patients with RyR1 mutations, as well as cellular and in vivo mouse models of the disease to characterise global cellular and mitochondrial Ca2+ signalling, mitochondrial function and gene expression associated with the disease. We show that RyR1 mutations that lead to the depletion of the channel are associated with increased IP3-mediated nuclear and mitochondrial Ca2+ signals and increased mitochondrial activity. Moreover, western blot and microarray analysis indicated enhanced mitochondrial biogenesis at the transcriptional and protein levels and was reflected in increased mitochondrial DNA content. The phenotype was recapitulated by RYR1 silencing in mouse cellular myotube models. Altogether, these data indicate that remodelling of skeletal muscle Ca2+ signalling following loss of functional RyR1 mediates bioenergetic adaptation.
PMID: 29701772 [PubMed - as supplied by publisher]
印刷用ページを開く Endnote用テキストダウンロード