INTRODUCTION: Aging impairs mitochondrial respiratory capacity and accelerates reactive oxygen species (ROS) accumulation, which promotes cellular senescence and disrupts skeletal muscle homeostasis. Mitochondria-derived oxidative stress can drive cellular senescence and contributes to muscle loss by compromising mitochondrial quality control mechanisms. Although previous studies have shown that intermittent elimination of p21high senescent cells has been shown to improve physical performance and extend lifespan in aged mice, it remains unclear whether the senescent cell clearance directly rejuvenates mitochondrial function, along with the associated alterations in mitophagy and mitochondrial biogenesis signaling in aged skeletal muscle. The present study aimed to determine whether genetic ablation of p21high senescent cells in old mice enhances mitochondrial respiratory capacity and restores mitochondrial quality control mechanisms. METHODS: Twenty-three-month-old p21-Cre transgenic mice were administered tamoxifen to induce Cre-mediated ablation of p21high senescent cells. Mitochondrial respiratory function was measured in permeabilized soleus muscle fibers using high-resolution Oroboros O2k respirometry system. Western blotting was conducted to evaluate mitochondrial quality control pathways, quantifying protein abundance of PINK1/Parkin-dependent and -independent mitophagy markers, mitochondrial biogenesis regulators, and oxidative phosphorylation (OXPHOS) complex proteins. RT-qPCR was performed to quantify transcriptional regulation of mitophagy- and biogenesis-related genes. Structural adaptations were assessed by measuring muscle fiber cross-sectional area using wheat germ agglutinin (WGA) staining. RESULTS: Intermittent elimination of p21high cells significantly enhanced mitochondrial oxidative phosphorylation capacity in aged muscle, particularly complex I+II-driven maximal (MAX) respiration. Senescent cell ablation markedly elevated protein abundance of the mitophagy initiator PINK1 and the PINK1/Parkin-independent mitophagy protein BNIP3L, alongside higher Pink1 and Park2 mRNA expression. LC3-II exhibited a trend toward elevation, whereas Parkin, OPTN, and Cathepsin D levels remained unchanged. Mitochondrial biogenesis markers were also enhanced, with significantly increased protein levels of PGC-1α and TFAM and a trend toward elevated NRF1. Among electron transport chain components, complex III (UQCRC2) was selectively increased. There were no changes in IL-6, TNF-α, NF-κB, or MnSOD. Morphological assessment revealed significantly greater muscle fiber cross-sectional area in senescent-cell-ablated mice, which indicates attenuation of age-related muscle atrophy. CONCLUSION: These findings demonstrate that p21high senescent cells contribute directly to age-related mitochondrial dysfunction in skeletal muscle and the targeted elimination of the senescent cells restores mitochondrial function through enhancement of mitochondrial quality control. Clearance of p21high cells stimulated both PINK1/Parkin-dependent and -independent mitophagy pathways and activated PGC-1α–NRF1–TFAM mitochondrial biogenesis signaling with selective elevation of complex III (UQCRC2). The combination of improved mitochondrial quality control, enhanced respiratory capacity, and preserved myofiber morphology provides strong mechanistic evidence that targeting p21high senescent cells is a potentially promising strategy to preserve mitochondrial health and muscle function during aging. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Noh et al. (Fri,) studied this question.