Abstract 12087: Autophagy is Essential for Enhanced Heart Function in Swimming Exercise-induced Cardiac Hypertrophy

Abstract

Exercise can induce physiological cardiac hypertrophy with normal or enhanced cardiac function. However, the molecular and cellular mechanisms underlying these effects remain incompletely understood. Autophagy is a cellular degradation pathway essential for maintaining cardiac homeostasis under various conditions. In this study, we investigated the functional role of autophagy in swimming exercise-induced cardiac effects. The GFP-LC3 (Microtubule-associated protein light chain 3) autophagy reporter mice were forced to swim 90 minutes twice a day. Swimming training at this intensity triggered the formation of GFP-LC3 puncta and increased the conversion of LC3-I to LC3-II in the heart. The number of GFP-LC3 puncta and the protein levels of LC3-II were further increased by the lysosomal inhibitor bafilomycin A1, indicating that swimming accelerated cardiac autophagic flux. We then subjected wild type (WT) mice and beclin 1 heterozygous knockout mice (BCN 1^+/-) to swimming exercise for 4 weeks. Both WT and BCN 1^+/- mice developed similar degree of cardiac hypertrophy as shown by a 20~% increase in the heart-weight to body-weight ratio, suggesting that autophagy is not essential for swimming-induced cardiac growth. Swimming training enhanced cardiac function in WT mice, but it compromised cardiac performance in BCN 1^+/- mice as demonstrated by the changes in fractional shortening (WT: sedentary 36.5±3.1 vs swim 45.7±5.6, p<0.01; BCN 1^+/- sedentary 39.4±4.4 vs swim 33.5±2.6, p<0.01). The impaired cardiac function in BCN 1^+/- mice was accompanied by increased oxidative injury and apoptosis as well as elevated expression of atrial natriuretic peptide and collagen 1, two markers commonly associated with pathological cardiac remodeling. In addition, both mitochondrial ATP synthase subunit ATP5G2 and ATP content were reduced in the BCN 1^+/- hearts after swimming, suggesting that insufficient autophagy undermined the capacity of mitochondria to produce ATP. These results were reproduced in mice that harbor gene trap-mediated hypomorphic alleles of ATG16L1 gene. Together, our data indicate that autophagy is dispensable for exercise-induced cardiac hypertrophy, but is required for the enhanced cardiac function.