PGC-1α is not mandatory for exercise- and training-induced adaptive gene responses in mouse skeletal muscle

Abstract

The aim of the present study was to test the hypothesis that peroxisome proliferator activated receptor-γ coactivator (PGC) 1α is required for exercise-induced adaptive gene responses in skeletal muscle. Whole body PGC-1α knockout (KO) and littermate wild-type (WT) mice performed a single treadmill-running exercise bout. Soleus and white gastrocnemius (WG) were obtained immediately, 2 h, or 6 h after exercise. Another group of PGC-1α KO and WT mice performed 5-wk exercise training. Soleus, WG, and quadriceps were obtained ∼37 h after the last training session. Resting muscles of the PGC-1α KO mice had lower (∼20%) cytochrome c (cyt c), cytochrome oxidase (COX) I, and aminolevulinate synthase (ALAS) 1 mRNA and protein levels than WT, but similar levels of AMP-activated protein kinase (AMPK) α1, AMPKα2, and hexokinase (HK) II compared with WT mice. A single exercise bout increased phosphorylation of AMPK and acetyl-CoA carboxylase-β and the level of HKII mRNA similarly in WG of KO and WT. In contrast, cyt c mRNA in soleus was upregulated in WT muscles only. Exercise training increased cyt c, COXI, ALAS1, and HKII mRNA and protein levels equally in WT and KO animals, but cyt c, COXI, and ALAS1 expression remained ∼20% lower in KO animals. In conclusion, lack of PGC-1α reduced resting expression of cyt c, COXI, and ALAS1 and exercise-induced cyt c mRNA expression. However, PGC-1α is not mandatory for training-induced increases in ALAS1, COXI, and cyt c expression, showing that factors other than PGC-1α can exert these adaptations.

Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training

“…Similarly, running time to exhaustion was~65-70% lower in the PGC-1α KO mice than in WT animals (Table 1b). These results are in accordance with previous studies demonstrating that endurance capacity was lower in PGC-1α KO animals than in WT (Leick et al 2008). Table 1a also shows that the intensity and duration of the training regimen followed by young and aged rats was enough to induce a significant improvement in maximal endurance capacity (~200% and~135%, respectively).…”

“…More commonly, it is estimated by the change in maximal activity, measured under optimal conditions in vitro, of a typical "marker enzyme" such as citrate synthase, or by the change in content of a single protein-like cytochrome C (Hood 2001;Terjung 1979). Several authors have used cytochrome C content as a marker of mitochondrial mass (Hood et al 2006;Leick et al 2008Leick et al , 2010 and this is the methodology that we have followed in the present work. Training caused an increase in cytochrome C content in WT but not in PGC-1α KO mice.…”

Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis

“…Whether these transient modifications of PGC-1␣ have an impact on RSV-mediated mitochondrial biogenesis remains to be determined. There is also considerable contention as to whether PGC-1␣ acts as a sole regulator of the induction of organelle synthesis in muscle, at least in response to exercise (20,(53)(54)(55). Thus, this raises the possibility that RSV may act through other mediators of mitochondrial biogenesis such as PGC-␤ or PGC-1␣-related coactivator.…”

PGC-1α Mediated Muscle Aerobic Adaptations to Exercise, Heat and Cold Exposure

“…However, loss-of-function studies using whole-body or muscle specific PGC-1α knock-out models have to date demonstrated contradictory results. Leick et al (2008) first showed that PGC-1α was not essential for exercise-induced mitochondrial biogenesis, where training-induced increases in COX1, Cyt c and δ-aminolevulinate synthase (ALAS) were not impaired in whole-body PGC-1α knock-out mice. Yet, whole-body PGC-1α deficiency is not an ideal model to study exercise-induced mitochondrial biogenesis in the skeletal muscle, as it is associated with numerous systemic effects, including hypermetabolism, hyperactivity and reluctance to exercise (Chinsomboon et al, 2009;Lin et al, 2004).…”

“…While there are many important factors involved in the biosynthesis of the mitochondrion, the transcriptional coactivator, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has been identified as a key regulator involved in this highly complex process Puigserver et al, 1998;Wu et al, 1999). Indeed, there is now good evidence demonstrating that exercise-induced mitochondrial biogenesis is modulated via PGC-1α dependant mechanisms (Calvo et al, 2008;Leick et al, 2010;Leick et al, 2008;Little et al, 2011;Safdar et al, 2011;Uguccioni and Hood, 2011;Zhang et al, 2014). Exercise capacity and performance has shown to be strongly associated with muscle mitochondrial content in both animal and human models (Daussin et al, 2008;Fitts et al, 1975) and is associated with improved risk factors for a variety of chronic diseases (Bishop-Bailey, 2013).…”