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PGC-1α regulates mitochondrial-sarcoplasmic reticulum (SR)-mediated calcium exchange, SR stress and cell death to mitigate skeletal muscle aging

Gill, Jonathan and Delezie, Julien and McGuirk, Shawn and Schnyder, Svenia and Gesa, Santos and Frank, Stephan and Rausch, Martin and Handschin, Christoph (2019) PGC-1α regulates mitochondrial-sarcoplasmic reticulum (SR)-mediated calcium exchange, SR stress and cell death to mitigate skeletal muscle aging. Aging cell. ISSN 1474-9726; 1474-9718

Abstract

Age-related impairment of muscle function severely affects the health of a growing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC-1α overexpression improves mitochondrial dynamics and calcium buffering in an estrogen-related receptor α (ERRα)-dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC-1α. As a result, PGC-1α prevents tubular aggregate formation and apoptosis of fibers in old muscle. Similarly, the pro-apoptotic effects of ceramide and thapsigargin were blunted by PGC-1α in muscle cells. Accordingly, mice with muscle-specific gain- and loss-of-function of PGC-1α exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC-1α on muscle function and overall health span in aging.

Item Type: Article
Date Deposited: 24 Jul 2019 00:45
Last Modified: 24 Jul 2019 00:45
URI: https://oak.novartis.com/id/eprint/37241

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