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. 2018 Feb;17(1):e12697.
doi: 10.1111/acel.12697. Epub 2017 Oct 25.

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

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

Jonathan F Gill et al. Aging Cell. 2018 Feb.

Abstract

The 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.

Keywords: PGC-1α; aging; exercise; mitochondria; motor function; sarcopenia; skeletal muscle.

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Figures

Figure 1
Figure 1
PGC‐1α levels determine exercise‐related mitochondrial improvements (a) Relative PGC‐1α gene expression in different muscles (n = 3–6). (b) Relative gastrocnemius mRNA levels of mitochondrial genes (n = 6). (c) Quadriceps mitochondrial OXPHOS protein levels (n = 6). (d) Mitochondrial mass quantified in gastrocnemius muscle (n = 6). Values are mean ± SEM. *p < .05; **p < .01; ****p < .0001 indicate statistically significant differences between sedentary and exercised animals of the same genotype, # p < .01; ## p < .01; ### p < .01; #### p < .001 indicate statistically significant differences between genotypes for sedentary and exercised animals
Figure 2
Figure 2
PGC‐1α potentiates exercise‐dependent endurance increase (a) Endurance level of mice challenged on a treadmill (n = 8–10). (b) Pre and postexercise blood lactate levels (n = 8–10). (c) Relative quadriceps mRNA levels of genes involved in lactate regulation and glycolysis (n = 4–6). (d) Representative pictures and quantification of fiber type staining of tibialis anterior muscles (red = type 1 fibers and cell membranes; blue = type 2A fibers; green = type 2B fibers; black = type 2X fibers). Scale bars represent 100 μm (n = 4–6). Values are mean ± SEM. *p < .05; **p < .01; ***p < .001; indicate statistically significant differences between sedentary and exercised animals of the same genotype, # p < .01; ## p < .01; ### p < .01; #### p < .001 indicate statistically significant differences between genotypes for sedentary and exercised animals, @@ p < 0.01; @@@@ p < 0.0001 indicate statistically significant differences pre‐ and post‐exhaustion
Figure 3
Figure 3
Absence of PGC‐1α accelerate sarcopenia (a) Maximal grip strength (n = 10–12). (b) Four limbs hanging time (n = 10–12). (c) Lean relative to body mass (n = 10). (d) Muscle mass relative to body weight (n = 5–6). (e) Tibialis anterior fiber type specific minimum ferret diameter (n = 3–4). Values are mean ± SEM. *p < .05; **p < .01; ***p < .001; ****p < .0001 indicate statistically significant differences between young and old animals of the same genotype. # p < .01; ## p < .01; #### p < 0.001 indicate statistically significant differences between genotypes of age‐matched animals
Figure 4
Figure 4
Exercise reduces premature sarcopenia in the absence of PGC‐1α (a) Maximal gip strength (n = 8–10). (b) Four limbs hanging time (n = 8–10). (c) Lean relative to body mass (n = 8–10). (d) muscle mass relative to body weight (n = 5–6). Values are mean ± SEM. *p < .05; **p < .01; indicate statistically significant differences between sedentary and exercised animals of the same genotype, # p < .01; ## p < .01; #### p < .001 indicate statistically significant differences between genotypes for sedentary and exercised animals
Figure 5
Figure 5
PGC‐1α delays locomotor dysfunction during aging (a) Balance performances measured during balance beam crossing (n = 10–12). (b) Motor coordination of mice challenged with a Rotarod (n = 10–12). (c) Relative mRNA levels of neuromuscular junction genes measured in tibialis anterior muscles (n = 5–6). Values are mean ± SEM. *p < .05; **p < .01; ***p < .001; ****p < .0001 indicate statistically significant differences between young and old animals of the same genotype. # p < .01; ## p < .01; ### p < .01; #### p < .001 indicate statistically significant differences between genotypes of age‐matched animals
Figure 6
Figure 6
PGC‐1α elevation mimic exercise to improve locomotor function in aged mice (a) Balance performances measured during balance beam crossing (n = 8–10). (b) Motor coordination of mice challenged with a Rotarod (n = 10). Values are mean ± SEM. *p < .05; **p < .01; indicate statistically significant differences between sedentary and exercised animals of the same genotype. # p < .01; ### p < .01; indicate statistically significant differences between genotypes for sedentary and exercised animals

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