G.P.84: Muscle physiology properties of mouse models for Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy is a severe muscle wasting disorder, caused by the loss of dystrophin. Since dystrophin is needed to maintain fiber stability during contractions, its absence results in fragile fibers, which are prone to exercise induced damage. In contrast to DMD patients, the mdx mouse model is less severely affected due, at least in part, to overexpression of the dystrophin homologue utrophin. To determine the role of utrophin in maintaining muscle strength and integrity, we performed in vivo force measurements in the tibialis anterior (TA) of 8week old dystrophic mice expressing utrophin on two ( mdx ), one ( mdx-utrn+/ −) or zero alleles ( mdx-utrn − / −). The specific force was significantly lower in all dystrophic compared to wild type mice, and mdx-utrn − / − mice performed significantly worse than mdx and mdx-utrn+/ − mice. Although mdx mice produced lower forces than wild type mice, the force frequency relationship curves followed a similar pattern. A substantial increase in force was observed upon stimulation with higher frequencies (>80Hz) in mdx mice. Contrastingly, lower frequencies ( mdx-utrn+/ − mice, while their maximum specific force was comparable to mdx mice. This suggested that the proportions of slow and fast fibers differed between the dystrophic models. Histologically, we confirmed a shift towards slow fibers in the TAs of mdx-utrn+/ − and −/− mice, whereas in mdx and wild type mice predominantly fast fibers were found. Eccentric (lengthening) contractions provoked a large force drop in mdx mice, while wild type mice were resistant. Interestingly, slow muscle fibers of mdx-utrn+/ − mice enabled better maintenance of force during eccentric contractions than seen in mdx mice. Mdx-utrn − / − mice did not show a drop in force as they were already very weak at protocol initiation. These results suggest that loss of utrophin provokes a shift towards slow fibers which partly preserves muscle function in heterozygotes.