Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1870, Issue 1, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2023.166859
Keywords
Cardiac hypertrophy; Physical exercise; Telomerase reverse transcriptase; Mitochondrial
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Physical exercise can prevent cardiac hypertrophy by upregulating mitochondrial TERT expression. Overexpression of mitochondrial-targeted TERT improves mitochondrial dysfunction and reduces oxidative stress, leading to the attenuation of cardiac hypertrophy.
Physical exercise is a non-pharmacological intervention that helps prevent pathological cardiac hypertrophy. However, the underlying molecular mechanisms remain unclear. Telomerase reverse transcriptase (TERT) has non-telomeric functions such as protection against mitochondrial dysfunction and oxidative stress, and its myocardial expression is upregulated by physical exercise. Here, we found that physical exercise caused myocardial upregulation of mitochondrial TERT and sustenance during transverse aortic constriction (TAC)induced cardiac hypertrophy. Overexpression of mitochondrial-targeted TERT (mito-TERT) via adeno-associated virus serotype 9 carrying the TERT-coding sequence fused with N-terminal mitochondrial-targeting sequence improved cardiac function and attenuated cardiac hypertrophy. Mechanistically, mito-TERT ameliorated mitochondrial dysfunction and oxidative stress, which were associated with improving the activity and subunit composition of complex I. Remarkably, the telomerase activator TA-65 also exhibited an antihypertrophic effect. Collectively, our results reveal a significant role for mito-TERT in mediating the antihypertrophic effect of physical exercise and demonstrate that TERT is a potential drug target for treating cardiac hypertrophy.
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