PGC-1α is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle

Abstract

Exercise confers numerous health benefits, many of which are thought to stem from exercise-induced mitochondrial biogenesis (EIMB) in skeletal muscle. The transcriptional coactivator PGC-1α, a potent regulator of metabolism in numerous tissues, is widely believed to be required for EIMB. We show here that this is not the case. Mice engineered to lack PGC-1α specifically in skeletal muscle (Myo-PGC-1αKO mice) retained intact EIMB. The exercise capacity of these mice was comparable to littermate controls. Induction of metabolic genes after 2 weeks of in-cage voluntary wheel running was intact. Electron microscopy revealed no gross abnormalities in mitochondria, and the mitochondrial biogenic response to endurance exercise was as robust in Myo-PGC-1αKO mice as in wildtype mice. The induction of enzymatic activity of the electron transport chain by exercise was likewise unperturbed in Myo-PGC-1αKO mice. These data demonstrate that PGC-1α is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle, in sharp contrast to the prevalent assumption in the field.

Figure 1. Mild decrease voluntary-wheel performance in Myo-PGC-1α animals.

A.) 10 to 12 week old Myo-PGC-1αKO mice and control littermates were individually housed in voluntary running wheel cages with electronic monitoring system for 2 weeks. Tracing of wheel activity, in revolutions per minute is shown. B.) Average number of revolutions per minute C.)Total distance ran in kilometers (km). Error bars indicate s.e.m.; n >6 per group in all panels. * - P<0.05 compared to control.

Figure 2. Induction of OXPHOS genes in Myo-PGC-1α animals.

A.) After overnight bout of voluntary running wheel, RNA was prepared from quadriceps muscles of the Myo-PGC-1αKO (red bar) and littermate controls (white bar), and the expression of the indicated genes measured by quantitative RT-PCR. B.) After 2 week bout of voluntary running wheel, RNA was prepared from quadriceps muscles of the Myo-PGC-1αKO (red bar) and littermate controls (white bar), and the expression of the indicated genes measured by quantitative RT-PCR. Error bars indicate s.e.m.; n >3 per group in all panels. * - P<0.05 compared to control; # - P<0.05 compared to sedentary.

Figure 3. Exercise induced mitochondrial biogenesis in Myo-PGC-1α animals.

A.) Schematic of mid-portion of muscle recruited in response to exercise. Shading represents oxidative portion of muscle. Black square represents region of interest (ROI) used for studies B.) Transmission electron micrographs (TEM) of transverse sections of recruited ROI of quadriceps before and after 2-week voluntary wheel run C.) Quantification of mitochondrial density from TEMsof the Myo-PGC-1αKO (red bar) and littermate controls (white bar).n>4 fields from 4 animals per group. Error bars indicate s.e.m.; n >3 per group in all panels. * - P<0.05 compared to control.

Figure 4. Intact Electron Complex Activity in Myo-PGC-1α in response to exercise.

A.) Enzymatic traces of complex activities B.) Rotenone sensitive NADH dehydrogenase activity (Complex I). C.) Succinate-cytochrome creductase activity (Complex II+III). D.) Glycerol-3-phosphate dehydrogenase + Complex III, rate dependent on glycerol-3-phosphate dehydrogenase (Complex III). E.) Cytochrome oxidase activity (Complex IV).F.) ATPase activity (Complex V). Myo-PGC-1αKO (red bar) and littermate controls (white bar). Error bars indicate s.e.m.; n >3 per group in all panels. * - P<0.05 compared to control; # - P<0.05 compared to sedentary.