Sites of Disruption in Dystrophic Muscle Following Eccentric Contractions

Abstract

PURPOSE: Dystrophin is responsible for maintaining plasmalemmal integrity and cellular homeostasis. A key feature of skeletal muscle that lacks dystrophin, as in the mdx mouse model for Duchenne muscular dystrophy (DMD), is a heightened sensitivity to eccentric (ECC) contraction-induced strength loss. However, the mechanisms responsible for the exaggerated loss of strength in dystrophic muscle have yet to be fully established. The purpose of this study was to determine possible sites within mdx muscle that are disrupted following ECC contractions. METHODS: Male wildtype and mdx mice (n = 8 per group) were chronically implanted with stimulating electrodes on the left common peroneal nerve and EMG electrodes on the left tibialis anterior (TA) muscle. The left anterior crural muscles (TA and extensor digitorum longus; EDL) of anesthetized mice performed 50 maximal ECC contractions. In vivo peak dorsiflexion torque and M-wave root mean square (RMS) were measured prior to and immediately after the ECC contractions. Following the in vivo assessment, the EDL was removed and ex vivo peak isometric force and caffeine-induced force were analyzed. RESULTS: Peak torque and force in wildtype mice were reduced 36 ± 4 and 28 ± 4% (p ≤ 0.001) following the ECC contractions, while no changes were observed in M-wave RMS (10 ± 2%; p = 0.49) or caffeine-induced force (10 ± 4%; p = 0.20). To the contrary, both M-wave RMS and caffeine-induced force were reduced in mdx muscle (60 ± 4 and 58 ± 5; p ≤ 0.001), and corresponded to reductions of 60 ± 2 and 67 ± 8% (p ≤ 0.001) in peak torque and force. CONCLUSIONS: On the basis of the disproportional reductions in strength measured in vivo and ex vivo (36 and 28%, respectively) compared with that of in vivo M-wave RMS (10%) and ex vivo caffeine-induced force (10%), we confirm that ECC contractions uncouple the plasmalemma from the ryanodine receptors (RyRs) in wildtype muscle. However, in mdx muscle, in vivo peak torque and M-wave RMS in addition to ex vivo force and caffeine-induced force were all reduced to a similar degree (58-67%), indicating that various sites were disrupted immediately following the injury. These data indicate strength loss in wildtype and mdx mice differ, in that plasmalemmal function and sites at or distal to the RyRs may all be impaired in dystrophic muscle following ECC contractions.