Wimberly Keon D, Kawaida Mia Y, Tice Abigail L, Luo Xiaoping, Lackey Jacob A, Alvarez Samuel, Wei-LaPierre Lan, Hepple Russell T, Ryan Terence E
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, United States.
Center for Exercise Science, University of Florida, Gainesville, Florida, United States.
J Appl Physiol (1985). 2025 Sep 1;139(3):839-848. doi: 10.1152/japplphysiol.00601.2025. Epub 2025 Sep 4.
Aging is associated with progressive declines in skeletal muscle mass, strength, and endurance, often linked to mitochondrial dysfunction. However, a complete understanding of mitochondrial impairments during aging is lacking. Herein, we examined how biological sex and aging affect muscle function and mitochondrial energy transduction. Male and female C57BL/6 mice at 16 and 26 mo of age ( = 48) were assessed for physical function, muscle contractility, histology, and mitochondrial bioenergetics. Using isolated limb muscle mitochondria, we used a diagnostic approach to evaluate respiration, redox potential, and membrane polarization under physiologically relevant energy demands. Aged mice had significantly lower grip strength ( = 2.7E-09), walking speed ( = 0.024), and endurance capacity ( = 1.24E-08). Muscle mass and contractile function were also significantly lower in 26-mo-old mice regardless of sex. Mitochondrial diagnostics revealed a significant reduction (30%-50%) in oxygen consumption rates across a range of energy demands and substrate conditions in both male and female 26-mo-old mice. Redox and membrane potentials were also reduced ( < 0.05) in aged mice, resulting in a lower respiratory efficiency when compared with 16-mo-old mice. Notably, aged males exhibited greater mitochondrial deficits with carbohydrate substrates, whereas aged females showed larger declines with fatty acid substrates. Aging induces diffuse impairments in mitochondrial energy transduction in skeletal muscle of mice of both sexes. The application of the mitochondrial diagnostics platform offers new insights into the changes in muscle mitochondria with aging and could enhance the identification of interventions for preserving mitochondrial health in aging. This study uses a mitochondrial diagnostic platform to understand how aging and biological sex impact mitochondrial energy transduction. Findings from this diagnostic approach revealed diffuse, but severe, deficits in energy transduction that occur across a broad range of substrate conditions. Given the lack of published data on female aging mice, the work helps fill a gap in the literature regarding sex-dependent and -independent alterations in muscle aging.
衰老与骨骼肌质量、力量和耐力的逐渐下降有关，这通常与线粒体功能障碍有关。然而，目前尚缺乏对衰老过程中线粒体损伤的全面了解。在此，我们研究了生物性别和衰老如何影响肌肉功能和线粒体能量转导。对16月龄和26月龄的雄性和雌性C57BL/6小鼠（每组n = 48）进行了身体功能、肌肉收缩性、组织学和线粒体生物能量学评估。我们使用分离的肢体肌肉线粒体，采用诊断方法评估在生理相关能量需求下的呼吸、氧化还原电位和膜极化。老年小鼠的握力（P = 2.7E-09）、行走速度（P = 0.024）和耐力（P = 1.24E-08）显著降低。无论性别，26月龄小鼠的肌肉质量和收缩功能也显著降低。线粒体诊断显示，在一系列能量需求和底物条件下，26月龄雄性和雌性小鼠的氧消耗率均显著降低（30%-50%）。老年小鼠的氧化还原电位和膜电位也降低（P < 0.05），与16月龄小鼠相比，呼吸效率更低。值得注意的是，老年雄性小鼠在以碳水化合物为底物时线粒体缺陷更大，而老年雌性小鼠在以脂肪酸为底物时下降幅度更大。衰老诱导两性小鼠骨骼肌线粒体能量转导出现弥漫性损伤。线粒体诊断平台的应用为衰老过程中肌肉线粒体的变化提供了新的见解，并可加强对衰老过程中线粒体健康保护干预措施的识别。本研究使用线粒体诊断平台来了解衰老和生物性别如何影响线粒体能量转导。这种诊断方法的结果显示，在广泛的底物条件下，能量转导存在弥漫但严重的缺陷。鉴于缺乏关于雌性衰老小鼠的已发表数据，这项工作有助于填补文献中关于肌肉衰老中性别依赖性和非依赖性改变的空白。
