Enhanced autophagy ameliorates cardiac proteinopathy. J Clin Invest 2013 Dec;123(12):5284-97
Date
11/02/2013Pubmed ID
24177425Pubmed Central ID
PMC3859422DOI
10.1172/JCI70877Scopus ID
2-s2.0-84890072367 (requires institutional sign-in at Scopus site) 242 CitationsAbstract
Basal autophagy is a crucial mechanism in cellular homeostasis, underlying both normal cellular recycling and the clearance of damaged or misfolded proteins, organelles and aggregates. We showed here that enhanced levels of autophagy induced by either autophagic gene overexpression or voluntary exercise ameliorated desmin-related cardiomyopathy (DRC). To increase levels of basal autophagy, we generated an inducible Tg mouse expressing autophagy-related 7 (Atg7), a critical and rate-limiting autophagy protein. Hearts from these mice had enhanced autophagy, but normal morphology and function. We crossed these mice with CryABR120G mice, a model of DRC in which autophagy is significantly attenuated in the heart, to test the functional significance of autophagy activation in a proteotoxic model of heart failure. Sustained Atg7-induced autophagy in the CryABR120G hearts decreased interstitial fibrosis, ameliorated ventricular dysfunction, decreased cardiac hypertrophy, reduced intracellular aggregates and prolonged survival. To determine whether different methods of autophagy upregulation have additive or even synergistic benefits, we subjected the autophagy-deficient CryABR120G mice and the Atg7-crossed CryABR120G mice to voluntary exercise, which also upregulates autophagy. The entire exercised Atg7-crossed CryABR120G cohort survived to 7 months. These findings suggest that activating autophagy may be a viable therapeutic strategy for improving cardiac performance under proteotoxic conditions.
Author List
Bhuiyan MS, Pattison JS, Osinska H, James J, Gulick J, McLendon PM, Hill JA, Sadoshima J, Robbins JMESH terms used to index this publication - Major topics in bold
AnimalsAutophagy
Autophagy-Related Protein 7
Cardiomyopathies
Crosses, Genetic
Disease Models, Animal
Doxorubicin
Gene Expression Regulation
Heart Failure
Mice
Mice, Transgenic
Microtubule-Associated Proteins
Muscle Proteins
Muscular Dystrophies
Myocytes, Cardiac
Physical Conditioning, Animal
Proteostasis Deficiencies
Recombinant Fusion Proteins
Ventricular Dysfunction
alpha-Crystallin B Chain