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. 2016 Dec 1;311(6):E928-E938.
doi: 10.1152/ajpendo.00209.2016. Epub 2016 Oct 25.

Adult expression of PGC-1α and -1β in skeletal muscle is not required for endurance exercise-induced enhancement of exercise capacity

Christopher Ballmann  1 , Yawen Tang  1   2 , Zachary Bush  1 , Glenn C Rowe  3   2
Affiliations

Adult expression of PGC-1α and -1β in skeletal muscle is not required for endurance exercise-induced enhancement of exercise capacity

Christopher Ballmann et al. Am J Physiol Endocrinol Metab. .

Abstract

Exercise has been shown to be the best intervention in the treatment of many diseases. Many of the benefits of exercise are mediated by adaptions induced in skeletal muscle. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators has emerged as being key mediators of the exercise response and is considered to be essential for many of the adaptions seen in skeletal muscle. However, the contribution of the PGC-1s in skeletal muscle has been evaluated by the use of either whole body or congenital skeletal muscle-specific deletion. In these models, PGC-1s were never present, thereby opening the possibility to developmental compensation. Therefore, we generated an inducible muscle-specific deletion of PGC-1α and -1β (iMyo-PGC-1DKO), in which both PGC-1α and -β can be deleted specifically in adult skeletal muscle. These iMyo-PGC-1DKO animals were used to assess the role of both PGC-1α and -1β in adult skeletal muscle and their contribution to the exercise training response. Untrained iMyo-PGC-1DKO animals exhibited a time-dependent decrease in exercise performance 8 wk postdeletion, similar to what was observed in the congenital muscle-specific PGC-1DKOs. However, after 4 wk of voluntary training, the iMyo-PGC-1DKOs exhibited an increase in exercise performance with a similar adaptive response compared with control animals. This increase was associated with an increase in electron transport complex (ETC) expression and activity in the absence of PGC-1α and -1β expression. Taken together these data suggest that PGC-1α and -1β expression are not required for training-induced exercise performance, highlighting the contribution of PGC-1-independent mechanisms.

Keywords: PGC-1; electron transport chain; exercise; skeletal muscle.

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Figures

Fig. 1.
Fig. 1.
Adult deletion of both PGC-1α and -1β decreases baseline ETC expression. A: PGC-1α and -1β mRNA expression in different skeletal muscle beds. Sol, soleus; TA, tibialis anterior; EDL, extensor digitorum longus; QUAD, quadriceps; DIA, diaphragm, TRI, triceps; GAS, gastrocnemius. B: PGC-1α and -1β mRNA expression in different non-skeletal muscle tissues. eWAT, epididymal white adipose tissue; BAT, brown adipose tissue; LIV, liver; LUN, lung; KID, kidney; BRA, brain; HRT, heart. C: ETC subunit mRNA expression. D: ETC protein expression. E: densitometry quantification of ETC protein expression normalized to nonspecific band (NSB) and relative to control. F: NADH dehydrogenase (Complex I) activity. G: succinate dehydrogenase/cytochrome-c reductase (Complex II-III) activity. H: cytochrome-c reductase (Complex III) activity. I: cytochrome-c oxidase (Complex IV) activity. J: ATP synthase (Complex V) activity from gastrocnemius (GAS) muscle of iMyo-PGC-1DKO and control littermates. Data are presented as means ± SE; n = 3–4 per group; *P < 0.05 compared with control as determined by unpaired t-test.
Fig. 2.
Fig. 2.
Adult deletion of PGC-1s in skeletal muscle decreases exercise performance. A: progressive endurance exercise exhaustion protocol. B: baseline time to exhaustion. C: total distance run. D: calculated total work in male and female iMyo-PGC-1DKO and control littermates. Data are presented as means ± SE; n = 5–7 per group; *P < 0.05 compared with control groups as determined by 2-way ANOVA with pairwise comparisons (Tukey adjustment).
Fig. 3.
Fig. 3.
Improvements in exercise performance with 4 wk of voluntary endurance training are PGC-1 independent. A: schematic of study design. B: longitudinal exercise stress test. C: percentage change relative to 4-wk time point for each genotype (circles, control animals; squares, iMyo-PGC1DKO animals; dashed lines, exercised groups). D: average day to day running distance. E: total running distance while on voluntary wheels for 4 wk training period. F: time to exhaustion. G: total distance run. H: calculated total work. Data are presented as means ± SE; n = 5–10 per group; *P < 0.05 compared with sedentary control; $P < 0.05 compared with exercised controls; #P < 0.05 compared with sedentary iMyo-PGC-1DKO animals as determined by 2-way ANOVA with pairwise comparisons (Tukey adjustment) for B, F–H.
Fig. 4.
Fig. 4.
Deletion of PGC-1s decreases ETC subunit gene expression but not protein expression. A: PGC-1 family mRNA expression. B: ETC subunit mRNA expression. C: representative Western blot of ETC protein expression. D: densitometry quantification of ETC protein expression normalized to Ponceau S (Ponc) staining from gastrocnemius (GAS) muscle of iMyo-PGC-1DKO and control littermates, exercised and sedentary. E: percent change in complex activity with exercise from sedentary animals. Data are presented as means ± SE; n = 5 per group; *P < 0.05 compared with sedentary control; #P < 0.05 compared with sedentary iMyo-PGC-1DKO animals as determined by 2-way ANOVA with pairwise comparisons (Tukey adjustment) for A, B–D.
Fig. 5.
Fig. 5.
ETC complex activity increases with exercise training independent of PGC-1 expression. A: NADH dehydrogenase (Complex I) activity. B: succinate dehydrogenase/cytochrome-c reductase (Complex II-III) activity. C: cytochrome-c reductase (Complex III) activity. D: cytochrome-c oxidase (Complex IV) activity. E: ATP synthase (Complex V) activity from gastrocnemius (GAS) muscle of iMyo-PGC-1DKO and control littermates, exercised and sedentary. F: percentage change from sedentary controls. Data are presented as means ± SE; n = 4–5 per group; *P < 0.05 compared with sedentary control; #P < 0.05 compared with sedentary iMyo-PGC-1DKO animals. P values were determined by 2-way ANOVA with pairwise comparisons (Tukey adjustment) for A–E.
Fig. 6.
Fig. 6.
PGC-1s may be necessary for exercise-induced mitochondrial biogenesis in adult skeletal muscle. A: schematic of recruited portion of quadriceps (QUAD) during exercise. B: representative electron micrograph images. C: quantification of mitochondrial index from electron micrographs. Data are presented as means ± SE; n = 5 animals per group; 20 images per animal; *P < 0.05 compared with sedentary control as determined by 2-way ANOVA with pairwise comparisons (Tukey adjustment).
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