Valproic acid reduces muscle susceptibility to contraction‐induced functional loss but increases weakness in two murine models of Duchenne muscular dystrophy

Dylan Moutachi (1, 2) , Mégane Lemaitre (1, 2) , Clément Delacroix (1, 2) , Onnik Agbulut (3) , Denis Furling (1, 2) , Arnaud Ferry (1, 4, 2)

1 Centre de recherche en Myologie – U974 SU-INSERM
2 Institut de Myologie
3 B2A-IBPS - Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing
4 UPCité - Université Paris Cité

Skeletal muscles in animal models of Duchenne muscular dystrophy (DMD) are more susceptible to contraction-induced functional loss, which is not related to fatigue. Valproic acid (VPA) reportedly improves serological and histological markers of damage in dystrophin-deficient murine muscle. Here, we tested whether VPA would reduce the susceptibility to contraction-induced functional loss in two murine DMD models. Adult female mdx (mild) and D2-mdx (severe) DMD murine models were administered VPA (240 mg/kg) or saline for 7 days. Some VPA-treated mdx mice also performed voluntary running in a wheel, which is known to reduce the susceptibility to contraction-induced functional loss, that is, isometric force drop following eccentric contractions. In situ muscle function was assessed before, during and after eccentric contractions. Muscle utrophin and desmin expression was also evaluated using immunoblotting. Interestingly, VPA reduced the isometric force drop following eccentric contractions in both murine models, without change in the relative eccentric maximal force and in the expression of utrophin and desmin. VPA for 7 days combined to voluntary running had no additive effect compared to VPA alone. Furthermore, VPA reduced the absolute isometric maximal force before eccentric contractions in both murine models. The results of our study indicated that VPA in both murine DMD models reduced the susceptibility to contraction-induced functional loss, but increased muscle weakness.

Mots clés: Duchenne muscular dystrophy; murine DMD models; muscle function; susceptibility to contraction-induced function loss; valproic acid

Domaines: Médecine humaine et pathologie; Pharmacologie

Dylan Moutachi, Mégane Lemaitre, Clément Delacroix, Onnik Agbulut, Denis Furling, et al.. Valproic acid reduces muscle susceptibility to contraction‐induced functional loss but increases weakness in two murine models of Duchenne muscular dystrophy. Clinical and Experimental Pharmacology and Physiology, In press, ⟨10.1111/1440-1681.13804⟩. ⟨hal-04146953⟩