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

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

BACKGROUND: 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, Lsq-1 and Civq-1, that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hind-limb ischemia. METHODS: 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. RESULTS: 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 Lsq-1 (C.B6-Lsq1-3). 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. BAG3Ile81, but not BAG3Met81, 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-BAG3Ile81 (n=9), but not BAG3Met81 (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 BAG3Met81, BAG3Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. CONCLUSIONS: 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.

Original languageEnglish (US)
Pages (from-to)281-296
Number of pages16
JournalCirculation
Volume136
Issue number3
DOIs
StatePublished - Jul 18 2017

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Autophagy
Muscular Diseases
Extremities
Muscles
Dependovirus
Ischemia
Green Fluorescent Proteins
Necrosis
Small Heat-Shock Proteins
Tissue Survival
Quantitative Trait Loci
Peripheral Arterial Disease
Middle Cerebral Artery
Femoral Artery
Stroke Volume
Muscle Cells
Ligation
Regeneration
Cell Differentiation
Histology

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

McClung, J. M., McCord, T. J., Ryan, T. E., Schmidt, C. A., Green, T. D., Southerland, K. W., ... Kontos, C. D. (2017). BAG3 (Bcl-2-Associated Athanogene-3) coding variant in mice determines susceptibility to ischemic limb muscle myopathy by directing autophagy. Circulation, 136(3), 281-296. https://doi.org/10.1161/CIRCULATIONAHA.116.024873

BAG3 (Bcl-2-Associated Athanogene-3) coding variant in mice determines susceptibility to ischemic limb muscle myopathy by directing autophagy. / McClung, Joseph M.; McCord, Timothy J.; Ryan, Terence E.; Schmidt, Cameron A.; Green, Tom D.; Southerland, Kevin W.; Reinardy, Jessica L.; Mueller, Sarah B.; Venkatraman, Talaignair N.; Lascola, Christopher D.; Keum, Sehoon; Marchuk, Douglas A.; Spangenburg, Espen E.; Dokun, Ayotunde; Annex, Brian H.; Kontos, Christopher D.

In: Circulation, Vol. 136, No. 3, 18.07.2017, p. 281-296.

Research output: Contribution to journalArticle

McClung, JM, McCord, TJ, Ryan, TE, Schmidt, CA, Green, TD, Southerland, KW, Reinardy, JL, Mueller, SB, Venkatraman, TN, Lascola, CD, Keum, S, Marchuk, DA, Spangenburg, EE, Dokun, A, Annex, BH & Kontos, CD 2017, 'BAG3 (Bcl-2-Associated Athanogene-3) coding variant in mice determines susceptibility to ischemic limb muscle myopathy by directing autophagy', Circulation, vol. 136, no. 3, pp. 281-296. https://doi.org/10.1161/CIRCULATIONAHA.116.024873
McClung, Joseph M. ; McCord, Timothy J. ; Ryan, Terence E. ; Schmidt, Cameron A. ; Green, Tom D. ; Southerland, Kevin W. ; Reinardy, Jessica L. ; Mueller, Sarah B. ; Venkatraman, Talaignair N. ; Lascola, Christopher D. ; Keum, Sehoon ; Marchuk, Douglas A. ; Spangenburg, Espen E. ; Dokun, Ayotunde ; Annex, Brian H. ; Kontos, Christopher D. / BAG3 (Bcl-2-Associated Athanogene-3) coding variant in mice determines susceptibility to ischemic limb muscle myopathy by directing autophagy. In: Circulation. 2017 ; Vol. 136, No. 3. pp. 281-296.
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T1 - BAG3 (Bcl-2-Associated Athanogene-3) coding variant in mice determines susceptibility to ischemic limb muscle myopathy by directing autophagy

AU - McClung, Joseph M.

AU - McCord, Timothy J.

AU - Ryan, Terence E.

AU - Schmidt, Cameron A.

AU - Green, Tom D.

AU - Southerland, Kevin W.

AU - Reinardy, Jessica L.

AU - Mueller, Sarah B.

AU - Venkatraman, Talaignair N.

AU - Lascola, Christopher D.

AU - Keum, Sehoon

AU - Marchuk, Douglas A.

AU - Spangenburg, Espen E.

AU - Dokun, Ayotunde

AU - Annex, Brian H.

AU - Kontos, Christopher D.

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N2 - BACKGROUND: 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, Lsq-1 and Civq-1, that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hind-limb ischemia. METHODS: 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. RESULTS: 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 Lsq-1 (C.B6-Lsq1-3). 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. BAG3Ile81, but not BAG3Met81, 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-BAG3Ile81 (n=9), but not BAG3Met81 (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 BAG3Met81, BAG3Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. CONCLUSIONS: 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.

AB - BACKGROUND: 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, Lsq-1 and Civq-1, that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hind-limb ischemia. METHODS: 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. RESULTS: 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 Lsq-1 (C.B6-Lsq1-3). 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. BAG3Ile81, but not BAG3Met81, 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-BAG3Ile81 (n=9), but not BAG3Met81 (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 BAG3Met81, BAG3Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. CONCLUSIONS: 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.

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