Upregulation of mitochondrial telomerase reverse transcriptase mediates the preventive effect of physical exercise on pathological cardiac hypertrophy via improving mitochondrial function and inhibiting oxidative stress

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.