Autophagy is an adaptive response in desmin-related cardiomyopathy

Paul Tannous, Hongxin Zhu, Janet L. Johnstone, John M. Shelton, Namakkal S. Rajasekaran, Ivor J. Benjamin, Lan Nguyen, Robert D. Gerard, Beth Levine, Beverly A. Rothermel, Joseph A. Hill

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

A missense mutation in the αB-crystallin (CryAB) gene triggers a severe form of desmin-related cardiomyopathy (DRCM) characterized by accumulation of misfolded proteins. We hypothesized that autophagy increases in response to protein aggregates and that this autophagic activity is adaptive. Mutant CryAB (CryABR120G) triggered a >2-fold increase in cardiomyocyte autophagic activity, and blunting autophagy increased the rate of aggregate accumulation and the abundance of insoluble CryABR120G- associated aggregates. Cardiomyocyte-restricted overexpression of CryAB R120G in mice induced intracellular aggregate accumulation and systolic heart failure by 12 months. As early as 2 months (well before the earliest declines in cardiac function), we detected robust autophagic activity. To test the functional significance of autophagic activation, we crossed CryABR120G mice with animals harboring heterozygous inactivation of beclin 1, a gene required for autophagy. Blunting autophagy in vivo dramatically hastened heart failure progression with a 3-fold increase in interstitial fibrosis, greater accumulation of polyubiquitinated proteins, larger and more extensive intracellular aggregates, accelerated ventricular dysfunction, and early mortality. This study reports activation of autophagy in DRCM. Further, our findings point to autophagy as an adaptive response in this proteotoxic form of heart disease.

Original languageEnglish (US)
Pages (from-to)9745-9750
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number28
DOIs
StatePublished - Jul 15 2008

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Desmin
Autophagy
Cardiomyopathies
Cardiac Myocytes
Systolic Heart Failure
Ventricular Dysfunction
Crystallins
Missense Mutation
Genes
Heart Diseases
Proteins
Fibrosis
Heart Failure
Mortality

Keywords

  • Protein aggregation
  • Remodeling

ASJC Scopus subject areas

  • General

Cite this

Tannous, P., Zhu, H., Johnstone, J. L., Shelton, J. M., Rajasekaran, N. S., Benjamin, I. J., ... Hill, J. A. (2008). Autophagy is an adaptive response in desmin-related cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America, 105(28), 9745-9750. https://doi.org/10.1073/pnas.0706802105
Tannous, Paul ; Zhu, Hongxin ; Johnstone, Janet L. ; Shelton, John M. ; Rajasekaran, Namakkal S. ; Benjamin, Ivor J. ; Nguyen, Lan ; Gerard, Robert D. ; Levine, Beth ; Rothermel, Beverly A. ; Hill, Joseph A. / Autophagy is an adaptive response in desmin-related cardiomyopathy. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 28. pp. 9745-9750.
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Tannous, P, Zhu, H, Johnstone, JL, Shelton, JM, Rajasekaran, NS, Benjamin, IJ, Nguyen, L, Gerard, RD, Levine, B, Rothermel, BA & Hill, JA 2008, 'Autophagy is an adaptive response in desmin-related cardiomyopathy', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 28, pp. 9745-9750. https://doi.org/10.1073/pnas.0706802105

Autophagy is an adaptive response in desmin-related cardiomyopathy. / Tannous, Paul; Zhu, Hongxin; Johnstone, Janet L.; Shelton, John M.; Rajasekaran, Namakkal S.; Benjamin, Ivor J.; Nguyen, Lan; Gerard, Robert D.; Levine, Beth; Rothermel, Beverly A.; Hill, Joseph A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 28, 15.07.2008, p. 9745-9750.

Research output: Contribution to journalArticle

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T1 - Autophagy is an adaptive response in desmin-related cardiomyopathy

AU - Tannous, Paul

AU - Zhu, Hongxin

AU - Johnstone, Janet L.

AU - Shelton, John M.

AU - Rajasekaran, Namakkal S.

AU - Benjamin, Ivor J.

AU - Nguyen, Lan

AU - Gerard, Robert D.

AU - Levine, Beth

AU - Rothermel, Beverly A.

AU - Hill, Joseph A.

PY - 2008/7/15

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N2 - A missense mutation in the αB-crystallin (CryAB) gene triggers a severe form of desmin-related cardiomyopathy (DRCM) characterized by accumulation of misfolded proteins. We hypothesized that autophagy increases in response to protein aggregates and that this autophagic activity is adaptive. Mutant CryAB (CryABR120G) triggered a >2-fold increase in cardiomyocyte autophagic activity, and blunting autophagy increased the rate of aggregate accumulation and the abundance of insoluble CryABR120G- associated aggregates. Cardiomyocyte-restricted overexpression of CryAB R120G in mice induced intracellular aggregate accumulation and systolic heart failure by 12 months. As early as 2 months (well before the earliest declines in cardiac function), we detected robust autophagic activity. To test the functional significance of autophagic activation, we crossed CryABR120G mice with animals harboring heterozygous inactivation of beclin 1, a gene required for autophagy. Blunting autophagy in vivo dramatically hastened heart failure progression with a 3-fold increase in interstitial fibrosis, greater accumulation of polyubiquitinated proteins, larger and more extensive intracellular aggregates, accelerated ventricular dysfunction, and early mortality. This study reports activation of autophagy in DRCM. Further, our findings point to autophagy as an adaptive response in this proteotoxic form of heart disease.

AB - A missense mutation in the αB-crystallin (CryAB) gene triggers a severe form of desmin-related cardiomyopathy (DRCM) characterized by accumulation of misfolded proteins. We hypothesized that autophagy increases in response to protein aggregates and that this autophagic activity is adaptive. Mutant CryAB (CryABR120G) triggered a >2-fold increase in cardiomyocyte autophagic activity, and blunting autophagy increased the rate of aggregate accumulation and the abundance of insoluble CryABR120G- associated aggregates. Cardiomyocyte-restricted overexpression of CryAB R120G in mice induced intracellular aggregate accumulation and systolic heart failure by 12 months. As early as 2 months (well before the earliest declines in cardiac function), we detected robust autophagic activity. To test the functional significance of autophagic activation, we crossed CryABR120G mice with animals harboring heterozygous inactivation of beclin 1, a gene required for autophagy. Blunting autophagy in vivo dramatically hastened heart failure progression with a 3-fold increase in interstitial fibrosis, greater accumulation of polyubiquitinated proteins, larger and more extensive intracellular aggregates, accelerated ventricular dysfunction, and early mortality. This study reports activation of autophagy in DRCM. Further, our findings point to autophagy as an adaptive response in this proteotoxic form of heart disease.

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