Effects of mitochondrial ABCB7 transporter upregulation on acute doxorubicin cardiorespiratory muscle injury

Doxorubicin (DOX) is a potent chemotherapeutic agent whose clinical utility is constrained by adverse off-target effects, including cardiotoxicity and respiratory muscle dysfunction. Mitochondrial ATP-binding cassette (ABC) transporters are hypothesized to play a role in drug clearance, iron homeostasis, and redox balance. Prior studies have implicated that the exercise-induced upregulation of mitochondrial ABC transporter, subfamily B member 7 (ABCB7), may confer protection against DOX-induced muscle injury. This study investigated whether ABCB7 overexpression in the heart and diaphragm could mitigate DOX-induced cardiorespiratory muscle dysfunction. Female Sprague-Dawley rats received an adeno-associated virus encoding ABCB7 (AAV9-MHCK7-h-ABCB7) or saline, followed by DOX (20 mg/kg) or saline treatment. The acute effects of DOX and ABCB7 on cardiac and respiratory function, mitochondrial DOX accumulation, and mitochondrial iron levels were assessed. ABCB7 overexpression did not attenuate DOX-induced cardiac dysfunction, evidenced by reduced fractional shortening, increased myocardial performance index, and elevated plasma cardiac injury biomarkers. However, ABCB7 overexpression partially preserved diaphragm contractility, independent of improvements in diaphragm rate of fatigue and ventilatory function. Cardiac and diaphragm overexpression of ABCB7 did not affect the mitochondrial levels of DOX, its primary metabolite doxorubicinol, or free iron in either tissue. Improved diaphragm force production was potentially related to an increase in mitochondrial catalase content. ABCB7 overexpression offered limited protection against DOX-induced respiratory muscle dysfunction and did not mitigate DOX-induced cardiac dysfunction. These findings suggest that ABCB7 alone is insufficient to prevent DOX-induced cardiorespiratory muscle injury.NEW & NOTEWORTHY The present study demonstrates that cardiac and diaphragm muscle overexpression of the mitochondrial ATP-binding cassette transporter ABCB7 is not sufficient to reduce the accumulation of the chemotherapeutic agent doxorubicin. Furthermore, increasing ABCB7 expression in the heart did not protect against doxorubicin cardiotoxicity, but did improve diaphragm contractility. This effect was potentially associated with improved antioxidant defenses. Future work should investigate alternative therapeutic targets with the potential to reduce off-target localization of doxorubicin and prevent myotoxicity.