BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy

Joseph M McClung; Timothy J McCord; Terence E Ryan; Cameron A Schmidt; Tom D Green; Kevin W Southerland; Jessica L Reinardy; Sarah B Mueller; Talaignair N Venkatraman; Christopher D Lascola; Sehoon Keum; Douglas A Marchuk; Espen E Spangenburg; Ayotunde Dokun; Brian H Annex; Christopher D Kontos

doi:10.1161/CIRCULATIONAHA.116.024873

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BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy

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BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy

Joseph M McClung, Timothy J McCord, Terence E Ryan, Cameron A Schmidt, Tom D Green, Kevin W Southerland, Jessica L Reinardy, Sarah B Mueller, Talaignair N Venkatraman, Christopher D Lascola, …

Circulation (New York, N.Y.), Vol.136(3), pp.281-296

07/18/2017

DOI: 10.1161/CIRCULATIONAHA.116.024873

PMCID: PMC5537727

PMID: 28442482

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Abstract

Critical limb ischemia is a manifestation of peripheral artery disease that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered 2 overlapping quantitative trait loci in mice, and , that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a variant (Ile81Met) segregates with tissue protection from hind-limb ischemia. We treated mice with either adeno-associated viruses encoding a control (green fluorescent protein) or 2 BAG3 (Bcl-2-associated athanogene-3) variants, namely Met81 or Ile81, and subjected the mice to hind-limb ischemia. We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of (C.B6- ). BALB/c mice treated with adeno-associated virus encoding the BL6 BAG3 variant (Ile81; n=25) displayed reduced limb-tissue necrosis and increased limb tissue perfusion compared with Met81- (n=25) or green fluorescent protein- (n=29) expressing animals. BAG3 , but not BAG3 , improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of adeno-associated virus-BAG3 (n=9), but not BAG3 (n=10) or green fluorescent protein (n=5), improved ischemic limb blood flow and limb muscle histology and restored muscle function (force production). Compared with BAG3 , BAG3 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the setting of ischemia.

Adaptor Proteins, Signal Transducing - genetics

Adaptor Proteins, Signal Transducing - metabolism

Animals

Apoptosis Regulatory Proteins - genetics

Apoptosis Regulatory Proteins - metabolism

Autophagy - genetics

Cell Line, Transformed

Genetic Variation - genetics

Hindlimb - blood supply

Hindlimb - pathology

Ischemia - genetics

Ischemia - pathology

Ischemia - prevention & control

Mice

Mice, Congenic

Mice, Inbred BALB C

Mice, Inbred C3H

Mice, Inbred C57BL

Muscular Diseases - genetics

Muscular Diseases - pathology

Muscular Diseases - prevention & control

Protein Binding - physiology

Details

Title: Subtitle: BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy
Creators: Joseph M McClung - East Carolina University
Timothy J McCord - Duke University
Terence E Ryan - University of Virginia
Cameron A Schmidt - East Carolina University
Tom D Green
Kevin W Southerland - Duke University
Jessica L Reinardy - Duke University
Sarah B Mueller - Duke University
Talaignair N Venkatraman - Duke University
Christopher D Lascola - Duke University
Sehoon Keum - Duke University
Douglas A Marchuk - Duke University
Espen E Spangenburg - East Carolina University
Ayotunde Dokun - University of Virginia
Brian H Annex - University of Virginia
Christopher D Kontos - Duke University
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.136(3), pp.281-296
DOI: 10.1161/CIRCULATIONAHA.116.024873
PMID: 28442482
PMCID: PMC5537727
NLM abbreviation: Circulation
ISSN: 0009-7322
eISSN: 1524-4539
Publisher: Lippincott Williams & Wilkins
Grant note: R00 HL103797 / NHLBI NIH HHS R01 HL121635 / NHLBI NIH HHS R01 HL124444 / NHLBI NIH HHS R01 HL116455 / NHLBI NIH HHS R01 AR066660 / NIAMS NIH HHS T32 GM007171 / NIGMS NIH HHS R01 HL130399 / NHLBI NIH HHS R56 HL124444 / NHLBI NIH HHS F32 HL129632 / NHLBI NIH HHS R21 HL118661 / NHLBI NIH HHS R01 HL125695 / NHLBI NIH HHS
Language: English
Date published: 07/18/2017
Academic Unit: Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984297497402771

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