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Aging Cell. 2019 Jul 10:e12993. doi: 10.1111/acel.12993. [Epub ahead of print]

Peroxisome proliferator-activated receptor γ coactivator 1α regulates mitochondrial calcium homeostasis, sarcoplasmic reticulum stress, and cell death to mitigate skeletal muscle aging.

Author information

1
Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, Basel, Switzerland.
2
Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.
3
Division of Neuropathology, Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
4
Biotherapeutic and Analytical Technologies, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.

Abstract

Age-related impairment of muscle function severely affects the health of an increasing 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-dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC-1α. As a result, PGC-1α prevents tubular aggregate formation and cell death pathway activation 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-of-function 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.

KEYWORDS:

PGC-1α; aging; calcium homeostasis; cell death; health span; mitochondria; skeletal muscle; tubular aggregates

PMID:
31290266
DOI:
10.1111/acel.12993
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