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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 7

Local delivery using intramuscular injection of recombinant annexin A6 protected against muscle damage in vivo.

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Local delivery using intramuscular injection of recombinant annexin A6 p...
(A) Tibialis anterior muscles of wild-type mice were injected i.m. with recombinant human annexin A6 (rANXA6) or vehicle control and subsequently injured with cardiotoxin injection. (B) Gross imaging revealed decreased Evans blue dye (blue) uptake in rANXA6-pretreated muscle compared with the contralateral control muscle. (C) Immunofluorescence imaging revealed decreased dye uptake (red) in muscle pretreated with rANXA6. Surface plots of dye uptake depict reduced fluorescence in muscle pretreated with rANXA6. White dotted lines outline the muscle sections. (D) Tibialis anterior (TA) muscle pretreated with rANXA6 had a significant reduction, approximately 50%, of Evans blue dye fluorescence over muscle area compared with control muscle. Scale bars: 1 mm. Data are expressed as mean ± SEM. Differences were assessed by 2-tailed t test. *P < 0.05 (n = 3 mice per condition). EBD, Evans blue dye.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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