PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

Abstract

SummaryThe age‐related impairment in muscle function results in a drastic decline in motor coordination and mobility in elderly individuals. Regular physical activity is the only efficient intervention to prevent and treat this age‐associated degeneration. However, the mechanisms that underlie the therapeutic effect of exercise in this context remain unclear. We assessed whether endurance exercise training in old age is sufficient to affect muscle and motor function. Moreover, as muscle peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) is a key regulatory hub in endurance exercise adaptation with decreased expression in old muscle, we studied the involvement of PGC‐1α in the therapeutic effect of exercise in aging. Intriguingly, PGC‐1α muscle‐specific knockout and overexpression, respectively, precipitated and alleviated specific aspects of aging‐related deterioration of muscle function in old mice, while other muscle dysfunctions remained unchanged upon PGC‐1α modulation. Surprisingly, we discovered that muscle PGC‐1α was not only involved in improving muscle endurance and mitochondrial remodeling, but also phenocopied endurance exercise training in advanced age by contributing to maintaining balance and motor coordination in old animals. Our data therefore suggest that the benefits of exercise, even when performed at old age, extend beyond skeletal muscle and are at least in part mediated by PGC‐1α.

PGC-1α regulates mitochondrial calcium homeostasis, SR stress and cell death to mitigate skeletal muscle aging

“…In parallel to improving calcium homeostasis and downregulation of proteins that accumulate in tubular aggregates such as CSQ1, a central role for PGC-1α in this context is further substantiated by our SDH staining and electron microscopy data as well as other studies that revealed a strong preference for tubular aggregate formation in glycolytic fibers (59,60). The potent effect of PGC-1α in driving an oxidative muscle fiber shift (32,33,61) thus likely further contributes to the inhibition of tubular aggregate formation. In light of our data, it would be interesting to study whether increased muscle PGC-1α levels prevent tubular aggregate formation in mice with tubular aggregateassociated myopathies (51,62).…”

“…7). In the light of our present and other recent findings (61,70,72), PGC-1α modulation, e.g. by exercise or pharmacological interventions, represents an attractive approach to reduce weakness, frailty and other pathological alterations associated with skeletal muscle aging, along with additional potential benefits on the heart (71).…”

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

“…In contrast, muscle‐specific PGC‐1α deletion led to a premature decrease in running capacity in 12‐month‐old mKO animals (Figure c). These data correlate with the balance, muscle strength, and fiber size changes upon PGC‐1α modulation in old animals (Gill, Santos, Schnyder, & Handschin, ). Together, these results clearly show that PGC‐1α is not only an essential regulator of mitochondrial function and dynamics in young and old animals, but also prevents the age‐associated decline of these systems.…”

“…In parallel to improving calcium homeostasis and downregulation of proteins that accumulate in tubular aggregates such as CSQ1, a central role for PGC‐1α in this context is further substantiated by our SDH staining and electron microscopy data as well as other studies that revealed a strong preference for tubular aggregate formation in glycolytic fibers (Funk et al, ). The potent effect of PGC‐1α in driving an oxidative muscle fiber shift (Gill et al, ; Handschin, Chin, et al, ; Lin et al, ) thus likely further contributes to the inhibition of tubular aggregate formation. In light of our data, it would be interesting to study whether increased muscle PGC‐1α levels prevent tubular aggregate formation in mice with tubular aggregate‐associated myopathies.…”

“…Accordingly, mKO‐PGC‐1α mice in many regards exhibit a premature aging phenotype (present results and ref. Gill et al, ). Along the same line, these animals have previously been reported to suffer from exacerbated age‐related glucose intolerance and systemic inflammation (Sczelecki et al, ).…”