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Recombinant annexin A6 promotes membrane repair and protects against muscle injury
Alexis R. Demonbreun, … , David Y. Barefield, Elizabeth M. McNally
Alexis R. Demonbreun, … , David Y. Barefield, Elizabeth M. McNally
Published September 23, 2019
Citation Information: J Clin Invest. 2019;129(11):4657-4670. https://doi.org/10.1172/JCI128840.
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Research Article Muscle biology Therapeutics

Recombinant annexin A6 promotes membrane repair and protects against muscle injury

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Abstract

Membrane repair is essential to cell survival. In skeletal muscle, injury often associates with plasma membrane disruption. Additionally, muscular dystrophy is linked to mutations in genes that produce fragile membranes or reduce membrane repair. Methods to enhance repair and reduce susceptibility to injury could benefit muscle in both acute and chronic injury settings. Annexins are a family of membrane-associated Ca2+-binding proteins implicated in repair, and annexin A6 was previously identified as a genetic modifier of muscle injury and disease. Annexin A6 forms the repair cap over the site of membrane disruption. To elucidate how annexins facilitate repair, we visualized annexin cap formation during injury. We found that annexin cap size positively correlated with increasing Ca2+ concentrations. We also found that annexin overexpression promoted external blebs enriched in Ca2+ and correlated with a reduction of intracellular Ca2+ at the injury site. Annexin A6 overexpression reduced membrane injury, consistent with enhanced repair. Treatment with recombinant annexin A6 protected against acute muscle injury in vitro and in vivo. Moreover, administration of recombinant annexin A6 in a model of muscular dystrophy reduced serum creatinine kinase, a biomarker of disease. These data identify annexins as mediators of membrane-associated Ca2+ release during membrane repair and annexin A6 as a therapeutic target to enhance membrane repair capacity.

Authors

Alexis R. Demonbreun, Katherine S. Fallon, Claire C. Oosterbaan, Elena Bogdanovic, James L. Warner, Jordan J. Sell, Patrick G. Page, Mattia Quattrocelli, David Y. Barefield, Elizabeth M. McNally

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Figure 6

Ca2+ dependency of the protective effects of recombinant annexin A6.

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Ca2+ dependency of the protective effects of recombinant annexin A6.
(A ...
(A and B) Wild-type myofibers were isolated and loaded with a fluorescence marker of membrane damage, FM 1-43 (green). Myofibers were pretreated with recombinant annexin A6 (rANXA6) and then damaged in 1 mM Ca2+ solution or 0 mM Ca2+ plus EGTA, a calcium chelator. FM 1-43 fluorescence uptake over time was significantly reduced at 1 mM Ca2+ compared with when EGTA was present. Scale bars: 5 μm. Data are expressed as mean ± SEM. Differences were tested by 2-way ANOVA with Bonferroni’s multiple-comparisons test. *P < 0.05 (n = 10 myofibers per condition; n = 3 mice per condition).

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