Diaz-Espinosa Jennifer, Stringer Kathleen A, Rosania Gus R
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA.
Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA.
Metabolites. 2023 May 19;13(5):671. doi: 10.3390/metabo13050671.
Mitochondrial health declines with age, and older patients can demonstrate dysfunction in mitochondrial-rich tissues, such as cardiac and skeletal muscle. Aged mitochondria may make older adults more susceptible to adverse drug reactions (ADRs). We assessed mitochondrial metabolic function by measuring two metabolites, l-carnitine and acetylcarnitine, to determine their effectiveness as candidate clinical biomarkers for age-related, drug-induced alterations in mitochondrial metabolism. To study age- and medication-related changes in mitochondrial metabolism, we administered the FDA-approved mitochondriotropic drug, clofazimine (CFZ), or vehicle for 8 weeks to young (4-week-old) and old (61-week-old) male C57BL/6J mice. At the end of treatment, whole blood and cardiac and skeletal muscle were analyzed for l-carnitine, acetylcarnitine, and CFZ levels; muscle function was measured via a treadmill test. No differences were found in blood or cardiac carnitine levels of CFZ-treated mice, but CFZ-treated mice displayed lost body mass and alterations in endurance and levels of skeletal muscle mitochondrial metabolites. These findings demonstrate the age-related susceptibility of the skeletal muscle to mitochondria drug toxicity. Since drug-induced alterations in mitochondrial metabolism in skeletal muscle were not reflected in the blood by l-carnitine or acetylcarnitine levels, drug-induced catabolism and changes in muscle function appear more relevant to stratifying individuals at increased risk for ADRs.
线粒体健康状况会随着年龄增长而下降,老年患者的富含线粒体的组织(如心肌和骨骼肌)可能会出现功能障碍。衰老的线粒体可能使老年人更容易发生药物不良反应(ADR)。我们通过测量两种代谢物——左旋肉碱和乙酰肉碱,来评估线粒体代谢功能,以确定它们作为与年龄相关的、药物诱导的线粒体代谢改变的候选临床生物标志物的有效性。为了研究线粒体代谢中与年龄和药物相关的变化,我们对年轻(4周龄)和年老(61周龄)的雄性C57BL/6J小鼠给予美国食品药品监督管理局(FDA)批准的亲线粒体药物氯法齐明(CFZ)或赋形剂,持续8周。在治疗结束时,分析全血、心肌和骨骼肌中的左旋肉碱、乙酰肉碱和CFZ水平;通过跑步机试验测量肌肉功能。接受CFZ治疗的小鼠的血液或心肌肉碱水平没有差异,但接受CFZ治疗的小鼠出现体重减轻、耐力改变以及骨骼肌线粒体代谢物水平变化。这些发现表明骨骼肌对线粒体药物毒性存在与年龄相关的易感性。由于骨骼肌中线粒体代谢的药物诱导改变未通过左旋肉碱或乙酰肉碱水平反映在血液中,药物诱导的分解代谢和肌肉功能变化似乎与对ADR风险增加的个体进行分层更相关。