Mitochondrial Remodeling During Physiological Cardiac Hypertrophy in the Burmese Python
Hannah R. Killian, Kyle G. Meador, Darrius M. Proctor, Kira M. Gressman1, Victoria A. Nuanes, Oliver J. Dansereau, Kendra L. Shattuck, Chanah K. Gallagher, Kari A. Santos, Tye D. Thaden, Jeannine M. Espinoza, Mary E. Banks, Emilio R. Dodier-Thurow, Claire M. Gillette, Ryan F. Lata, Joshua L. Miller, Cecilia A. Riquelme, Leslie A. Leinwand, Pamela A. Harvey

Abstract
I. Background: Cardiac hypertrophy occurs in response to both pathological and physiological stimuli, with the latter providing a beneficial effect on cardiac function. In pathological hypertrophy, mitochondrial dysfunction occurs due to oxidative stress, however, in physiological hypertrophy, sustained energy production is supported by either mitochondrial biogenesis or via enlargement of existing mitochondria. To date, there are no approved drugs to address mitochondrial dysfunction in heart failure. Thorough characterization of the signaling and genetic profiles involved in metabolic remodeling during physiological hypertrophy could shed light on novel drug targets that support energy production and potentially reverse metabolic dysfunction in the failing heart. II. Methods and Results: Electron microscopy revealed increased area occupied and redistribution of mitochondria in the Burmese python ventricle, a model of physiological hypertrophy, after feeding. Measurement of phosphorylation states of 46 signaling molecules was performed and demonstrated activation of signaling pathways that mediate both cardiac hypertrophy and mitochondrial biogenesis. To validate that mitochondrial biogenesis is occurring, expression of 15 genes involved in mitochondrial biogenesis, mitochondrial function, and termination of mitochondrial biogenesis was measured. Dynamic expression was observed during hypertrophy and regression, consistent with mitochondrial biogenesis. III. Conclusions: The results suggest that physiologic cardiac hypertrophy is supported by activation of signaling pathways that mediate mitochondrial biogenesis in the Burmese python heart. The patterns of gene expression are consistent with this observation. Data presented here represent a broad view of physiological metabolic remodeling in the heart as well as possible novel targets to support contractility of the failing heart.

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