Aging-Related Myocardial Susceptibility Lowers Cardiac Tolerance to Chronic Intermittent Hypoxia Through Dynamin-Related Protein 1-Associated Mitochondrial Vulnerability.

Abstract

Chronic intermittent hypoxia (CIH), a cardinal pathophysiological feature of obstructive sleep apnea (OSA), repeatedly exposes the heart to hypoxia-reoxygenation stress. The cardiac outcome of CIH, however, may depend on the biological state of the target myocardium. Here, we investigated whether a pre-existing aging-related myocardial susceptibility lowers the tolerance threshold for CIH-induced injury and whether Dynamin-related protein 1 (Drp1) contributes to the enhanced vulnerability of senescence-like cardiomyocytes under CIH. Using G3 Tert-deficient (Tert^-/-) mice and D-galactose (D-gal)-induced senescence-like primary cardiomyocytes, we show that aging-related susceptibility consistently amplifies CIH-induced cardiac injury. In young wild-type mice, 8 weeks CIH induced early cardiac remodeling and senescence-associated myocardial stress without overt systolic decompensation. In Tert^-/- mice, the same CIH exposure shifted the cardiac response further toward maladaptive remodeling. Compared with CIH alone, EF and FS were reduced by an additional 24.6% and 15.8%, respectively. In senescence-like cardiomyocytes, CIH amplified mitochondrial vulnerability, with impaired energy production, elevated mitochondrial oxidative stress, and a fission-biased mitochondrial dynamics marker profile. Drp1 knockdown did not fully reverse this mitochondrial state but restored 55.1% of the CIH + D-gal induced ATP decline and reversed 47.4% of the mitochondrial ROS excess, while attenuating DNA damage response activation and senescence-associated signaling. These findings indicate that aging-related myocardial susceptibility is not a passive contextual factor in CIH-induced injury but a biological state that actively shapes the cardiac response to repeated hypoxia-reoxygenation stress. Drp1-associated mitochondrial dynamics imbalance may represent a functional link between diminished mitochondrial stress tolerance and amplified cardiomyocyte vulnerability.