Rescue of Dystrophic Skeletal Muscle by PGC-1α Involves a Fast to Slow Fiber Type Shift in the mdx Mouse

Abstract

Increased utrophin expression is known to reduce pathology in dystrophin-deficient skeletal muscles. Transgenic over-expression of PGC-1α has been shown to increase levels of utrophin mRNA and improve the histology of mdx muscles. Other reports have shown that PGC-1α signaling can lead to increased oxidative capacity and a fast to slow fiber type shift. Given that it has been shown that slow fibers produce and maintain more utrophin than fast skeletal muscle fibers, we hypothesized that over-expression of PGC-1α in post-natal mdx mice would increase utrophin levels via a fiber type shift, resulting in more slow, oxidative fibers that are also more resistant to contraction-induced damage. To test this hypothesis, neonatal mdx mice were injected with recombinant adeno-associated virus (AAV) driving expression of PGC-1α. PGC-1α over-expression resulted in increased utrophin and type I myosin heavy chain expression as well as elevated mitochondrial protein expression. Muscles were shown to be more resistant to contraction-induced damage and more fatigue resistant. Sirt-1 was increased while p38 activation and NRF-1 were reduced in PGC-1α over-expressing muscle when compared to control. We also evaluated if the use a pharmacological PGC-1α pathway activator, resveratrol, could drive the same physiological changes. Resveratrol administration (100 mg/kg/day) resulted in improved fatigue resistance, but did not achieve significant increases in utrophin expression. These data suggest that the PGC-1α pathway is a potential target for therapeutic intervention in dystrophic skeletal muscle.

Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis

“…Interestingly, as this article was in preparation, it was shown that chronic RSV administration also tended to increase utrophin A protein content in dystrophic skeletal muscle (56). Around the same time, others found that while RSV treatment induced utrophin A mRNA expression, the drug had no effect on utrophin A protein levels (19,20).…”

“…In a preclinical model of DMD, treatment of mdx mice with RSV evokes beneficial adaptations in skeletal muscle (19,20,29,56). However, data on whether RSV induces skeletal muscle remodeling in mdx animals toward slower, more oxidative characteristics are clearly lacking and remain fragmentary.…”

“…However, data on whether RSV induces skeletal muscle remodeling in mdx animals toward slower, more oxidative characteristics are clearly lacking and remain fragmentary. One study demonstrated that treatment of mdx mice with RSV for 8 wk at 100 mg·kg Ϫ1 ·day Ϫ1 enhanced fatigue resistance to ex vivo contractions in the SOL muscle (56), while in another study, the same dose administered for a short 10-day time course increased SIRT1, PGC-1␣, and utrophin A mRNA expression in the GAST muscle but did not affect the protein content of these factors (20). Furthermore, Gordon et al (19) recently showed that RSV exposure for 8 wk had no effect on skeletal muscle mitochondrial content or utrophin A expression.…”

“…Notably, this latter point is cause for debate (24,25,28,50,51,61). In recent years, treatment of dystrophic mdx mice with RSV was shown to result in beneficial adaptations (19,20,29,56). However, it is largely unknown whether chronic RSV administration promotes expression of the slow, oxidative phenotype in dystrophic skeletal muscle, as it does in muscles of wild-type animals, which could mitigate the dystrophic pathology (36,37,44,60).…”

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy

“…Force generation at 90 and 100 Hz did not differ in any muscle studied, and the force was normalized to the isometric tetanus at 100 Hz to generate force-frequency curves. Second, soleus muscles were subjected to a fatigue test, as previously described (34). Briefly, muscles were stimulated once per second for 10 min (200-s pulse, 100 Hz, 330-ms duration) to determine resistance to fatigue.…”