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bioRxiv · 10.1101/2021.11.29.470495

SR Ca2+ handling in unbranched, immediately post-necrotic fast-twitch mdx fibres is similar to wt littermates

Chan, S.·Kueh, S. L. L.·Morley, J. W.·Head, S.
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Abstract

There is a lack of consensus in the literature regarding the effects of dystrophin deficiency on the Ca2+-handling properties of the SR in mdx mice, an animal model of Duchenne muscular dystrophy. One possible reason for this is that only a few studies control for the presence of branched fibres. Fibre branching, a consequence of degenerative-regenerative processes such as muscular dystrophy, has in itself a significant influence on the function of the SR. In our present study we attempt to detect early effects of dystrophin deficiency on SR Ca2+ handling by using unbranched fibres from the immediate post-necrotic stage in mdx mice (just regenerated following massive necrosis). Using kinetically-corrected Fura-2 fluorescence signals measured during twitch and tetanus, we analysed the amplitude, rise time and decay time of {Delta}[Ca2+]i in unfatigued and fatigued fibres. Decay was also resolved into SR pump and SR leak components. Fibres from mdx mice were similar in all respects to fibres from wt littermates apart from: (i) a longer rise time and slower rate of rise of [Ca2+]i during a tetanus; and (ii) a mitigation of the fall in {Delta}[Ca2+]i amplitude during the course of fatigue. Our findings suggest that the early effects of a loss of dystrophin on SR Ca2+ handling are only slight, and differ from the widely held view that there is significant Ca2+ pathology in mdx mice. It may be that Ca2+ pathology is magnified by progressive branching and degeneration. New findingsCentral question: What are the early effects of dystrophin deficiency on SR Ca2+ handling in the mdx mouse? Main finding: In the mdx mouse, Ca2+ handling by the SR is little affected by the absence of dystrophin when looking at fibres without branches that have just regenerated following massive myonecrosis. This has important implications for the traditional view that Ca2+ pathology is significant in the mdx mouse.

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Chan, S., Kueh, S. L. L., Morley, J. W., Head, S.. 2021-12-01. SR Ca2+ handling in unbranched, immediately post-necrotic fast-twitch mdx fibres is similar to wt littermates. https://doi.org/10.1101/2021.11.29.470495

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