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.
Highlights
Since equal amounts of isolated mitochondria (275 μg) were used for these measurements, the results indicate that when normalized to mitochondrial amount, mitochondria from mTg‐PGC‐1α animals have an improved intrin‐ sic calcium buffering capacity compared to mitochondria from WT mice
We describe here a novel PGC‐1α‐regulated pathway involving the collective control of the function and interaction between mito‐ chondria and the sarcoplasmic re‐ ticulum (SR) centered on calcium homeostasis
Our findings provide a mechanistic and functional link between the observed decline in PGC‐1α expression and the ensuing reduction in mitochondrial dynamics and activity in muscle at old age that have been reported previously
Summary
Muscle strength and mass progressively decline with age, leading to physical disability, and higher morbidity and mortality. The genes encoding proteins related to calcium exchange that form an organelle‐spanning complex to control mitochondria‐SR interactions at MAMs were all downregulated in old WT mice, and rescued in old mTg‐PGC‐1α animals, including Itpr on the SR side, Grp pro‐ viding a link between SR and mitochondria, and Vdac on the mito‐ chondrial side The tethering of this complex to both organelles is supported by the additional link provided by the mitofusins, which exhibit a similar regulation. In addition to the tubular aggregates, electron microscopy revealed other age‐linked, abnor‐ mal structures of unknown origin and function in muscles fibers of old mKO‐PGC‐1α and WT mice that were absent from the young animals of all three genotypes and from old mTg‐PGC‐1α mice (Figure S4d), indicating further age‐associated abnormalities and damage in skeletal muscle that can be prevented by high levels of PGC‐1α.
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