Age and basal respiratory capacity influence skeletal muscle OXPHOS responses to MitoQ

Background: Skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS), the process by which mitochondria generate ATP, is essential for muscle function and metabolic homeostasis. Multiple lines of evidence demonstrate that aging is associated with mitochondrial dysfunction; however, the direct effect of aging on OXPHOS remains equivocal. Despite the equivocal effects of aging on OXPHOS itself, aging muscle often exhibits elevated mitochondrial reactive oxygen species (mtROS) and redox imbalance. This provides a biological rationale for testing whether decreasing mitochondrial reactive oxygen species (mtROS) with MitoQ can improve multiple parameters associated with mitochondrial function. Targeting mitochondrial-derived ROS (mtROS) with mitochondrial-targeted antioxidants (e.g., MitoQ) may be an effective therapeutic strategy to improve skeletal muscle OXPHOS and limit mtROS. Additionally, the effect of these mitochondrial-targeted antioxidants may be influenced by basal mitochondrial respiratory capacity or mtROS production rather than age, per se. We hypothesized that MitoQ supplementation would improve skeletal muscle mitochondrial respiration, with greater enhancements in adults with lower baseline respiratory capacity, independent of age. Methods: Twenty-one younger (n=21; 10M/11F; 26 ± 6 y) and twenty older (n=20; 10M/10F; 66 ± 7 y) adults underwent skeletal muscle biopsies before (pre) and after 2 weeks (post) of either 40 mg/day of MitoQ or placebo. Mitochondrial respiration, including state 3 (complex I (CI), complex II (CII), combined CI+II OXPHOS), and state 4 (leak respiration), along with H 2 O 2 production, was assessed using high-resolution respirometry. Finally, Western blots were performed to assess protein expression before and after 2 weeks of supplementation. Results: At baseline, older adults showed higher state 4 respiration compared with younger adults (p ˂ 0.001), whereas no group differences were observed for state 3 CI, CII, or combined CI+II OXPHOS (p > 0.05). Baseline H 2 O 2 production did not differ between groups (p = 0.117). Older adults exhibited lower Electron Transport Chain (ETC) protein expression of CI and CII compared to younger adults (both p < 0.001), while the expression of other complexes was not different. Following 2 weeks of supplementation, MitoQ improved state 3 respiration such that higher state 3 CI (Pre: 11.27 ± 10.33 vs Post: 15.82 ± 11.34 pmol·s-1·mg-1, Δ +4.54), state 3 CII (Pre: 42 ± 9.71 vs Post: 52.5 ± 9.76 pmol·s-1·mg-1, Δ +10.5), and state 3 CI+II OXPHOS (Pre: 59.2 ± 10.53 vs Post: 71.8 ± 12.06 pmol·s-1·mg-1, Δ +12.5) (all p ˂ 0.05), were observed in younger but not older adults. Baseline state 3 CI+II OXPHOS was strongly correlated with the change in CI+II OXPHOS following MitoQ supplementation (r = -0.67, p = 0.001). Age was also correlated with the change in CI+II OXPHOS (r = -0.49, p = 0.024). Baseline CI+II OXPHOS remained correlated with the change in CI+II OXPHOS with MitoQ (r = -0.76, p = 0.010) in older adults when separated by age. Additionally, baseline CI protein expression (r = -0.79, p = 0.008) and baseline 4HNE (r = -0.74, p = 0.015) were likewise associated with the change in CI+II OXPHOS following MitoQ supplementation in older adults. Conclusions: These data indicate that the potential MitoQ-enhancing effects on skeletal muscle CI+II OXPHOS are influenced to a greater extent by baseline respiratory capacity rather than age. Furthermore, these data suggest that individuals with lower basal CI+II OXPHOS or greater redox imbalance may exhibit the greatest benefit from mitochondria-targeted antioxidants such as MitoQ. Funding source: 5R01HL142603-05 (JDT), I01RX003810 (JDT, RSR) 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.