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Exogenous administration of a PPARδ agonist to dystrophic mdx mice confers no protection from contraction-mediated muscle damage

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by a variety of mutations in the dystrophin gene leading to the absence of dystrophin, a cytoskeleton protein implicated in muscle fibre stability. The lack of dystrophin renders muscle fibres highly susceptible to lengthening contraction-induced damage; a contributing mechanism to the dystrophic pathology (Lynch, 2004). Protecting dystrophic muscle fibres from injury is an important therapeutic strategy for DMD. Fast-twitch muscles are more susceptible to contraction-mediated damage than slow-twitch fibres in healthy and dystrophic mice (Consolino & Brooks, 2004), and so altering muscle fibre composition could potentially decrease injury susceptibility. Transgenic over-expression of peroxisome-proliferator activated receptor delta (PPARδ) in skeletal muscles increased the proportion of slow-twitch type I muscle fibres and treating mice with the PPARδ agonist, GW501516, promoted a slow-muscle phenotype and mitochondrial biogenesis, indicative of a shift to higher proportions of type I muscle fibres (Wang et al., 2004). We tested the hypothesis that treating dystrophic mdx mice with GW501516 would confer protection to muscles from contraction-induced injury by inducing a shift towards a slower muscle phenotype.

Dystrophic mdx mice (12 weeks old) were treated with GW501516 (10 mg/kg, oral gavage) for 4 weeks. Mice were anaesthetised deeply (60 mg/kg, sodium pentobarbital) for assessment of contractile function. Susceptibility to contraction-induced injury was examined in situ in the tibialis anterior (TA) muscle, and in vitro in soleus and diaphragm muscles. Muscle fatigability was examined in vitro in the extensor digitorum longus (EDL), soleus, and diaphragm muscles using a standard four-minute fatiguing stimulation protocol. The mice were killed by cardiac excision while anaesthetised.

Treating mdx mice with the PPARδ agonist did not alter the susceptibility to contraction-induced injury in the muscles tested. Maximum force (P_o) was reduced in the TA muscle after treatment. Muscle fatiguability was unchanged in the EDL and diaphragm muscles, however, the soleus muscles were more fatigue resistant after treatment (p < 0.05). These results indicate that a minor shift to a slower muscle phenotype does not confer protection to dystrophic muscles from contraction-induced injury.

Consolino CM & Brooks SV. (2004) Journal of Applied Physiology , 96: 633-8.

Lynch GS. (2004) Clinical and Experimental Pharmacology and Physiology, 31: 557-61.

Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham J, Kang H, & Evans RM. (2004) PLOS Biology, 2: e294.