Effects of calpain inhibition in excitation‐contraction coupling properties in dystrophic muscle exposed to fatiguing contractions

Abstract

Duchenne muscular dystrophy (DMD) is the most severe type of muscular dystrophy affecting humans. Alterations in intracellular calcium (Ca2+) are thought to play an important role in skeletal muscle weakness in DMD due to the activation of Ca2+‐regulated proteases (calpains).Purposeto evaluate if impairments in Ca2+ regulation are exacerbated in muscle from three mouse models of DMD and if calpain inhibition could attenuate the muscle weakness induced by fatiguing contractions.Methodscontrol (C57BL10/ScSn; n=3), mdx (n=5), mdx/Utr+/− (n=6), and mdx/Utr−/− (n=4) mice were used in the present study. The flexor digitorum brevis single muscle fibres (SMF) were obtained by collagenase digestion and loaded with Fura‐2 AM to evaluate resting [Ca2+]i, peak [Ca2+]i, and time to fatigue with and without a calpain inhibitor (ALLN).Resultsresting [Ca2+]i was higher in two dystrophic mouse models (mdx and mdx/Utr+/−) compared to the control (CON) group (p<0.05). No differences were reported in peak [Ca2+]i or time to fatigue. However, dystrophic fibres (all groups) exposed to ALLN were able to maintain their pre‐fatigue [Ca2+]i levels compared to Vehicle‐treated fibres (p<0.05). These data suggest that calpain activation leads to the reduction in [Ca2+]i observed after fatiguing tetani and therefore likely contributes to muscle weakness following a bout of muscle contractions in DMD.