4-hydroxy-2-nonenal and Sarcopenia

Recent evidence suggests that impaired mitophagy, a process in charge of removing damaged/dysfunctional mitochondria and in part regulated by Parkin, could contribute to the ageing-related loss of muscle mass and function. In the present study, we show that Parkin overexpression attenuates ageing-related loss of muscle mass and strength and unexpectedly causes hypertrophy in adult skeletal muscles. We also show that Parkin overexpression leads to increases in mitochondrial content and enzymatic activities. Finally, our results show that Parkin overexpression protects from ageing-related increases in markers of oxidative stress, fibrosis and apoptosis. Our findings place Parkin as a potential therapeutic target to attenuate sarcopenia and improve skeletal muscle health and performance.. The ageing-related loss of muscle mass and strength, a process called sarcopenia, is one of the most deleterious hallmarks of ageing. Solid experimental evidence indicates that mitochondrial dysfunctions accumulate with ageing and are critical in the sarcopenic process. Recent findings suggest that mitophagy, the process in charge of the removal of damaged/dysfunctional mitochondria, is altered in aged muscle. Impaired mitophagy represents an attractive mechanism that could contribute to the accumulation of mitochondrial dysfunctions and sarcopenia. To test this hypothesis, we investigated the impact of Parkin overexpression in skeletal muscles of young and old mice. Parkin was overexpressed for 4 months in muscles of young (3 months) and late middle-aged (18 months) mice using i.m. injections of adeno-associated viruses. We show that Parkin overexpression increased muscle mass, fibre size and mitochondrial enzyme activities in both young and old muscles. In old mice, Parkin overexpression increased muscle strength, peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) and mitochondrial density. Parkin overexpression also attenuated the ageing-related increase in 4-hydroxynonenal content (a marker of oxidative stress) and type I collagen content (a marker of fibrosis), as well as the number of terminal deoxynucleotidyl transferase dUTP nick-end labelling-positive myonuclei (a marker of apoptosis). Overall, our results indicate that Parkin overexpression attenuates sarcopenia and unexpectedly causes hypertrophy in adult muscles. They also show that Parkin overexpression leads to increases in mitochondrial content and enzymatic activities. Finally, our results show that Parkin overexpression protects against oxidative stress, fibrosis and apoptosis. These findings highlight that Parkin may be an attractive therapeutic target with respect to attenuating sarcopenia and improving skeletal muscle health and performance.

Topics: Aging; Aldehydes; Animals; Apoptosis; Collagen Type I; Male; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle Strength; Muscle, Skeletal; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Sarcopenia; Ubiquitin-Protein Ligases

Oxidative stress and mitochondrial dysfunction are associated with the aging process. However, the role of nuclear factor erythroid 2 -related factor 2 (Nrf2) in skeletal muscle during aging remains to be clarified. In the current study, we assessed whether the lack of Nrf2, which is known as a master regulator of redox homeostasis, promotes age-related mitochondrial dysfunction and muscle atrophy in skeletal muscle. Here, we demonstrated that mitochondrial 4-hydroxynonenal and protein carbonyls, markers of oxidative stress, were robustly elevated in aged Nrf2 knockout (KO) mice because of the decreased expression of Nrf2-target antioxidant genes. Mitochondrial respiration declined with aging; however, there was no difference between Nrf2 KO and age-matched WT mice. Similarly, cytochrome c oxidase activity was lower in aged WT and Nrf2 KO mice compared with young WT mice. The expression of Mfn1 and Mfn2 mRNA was lower in aged Nrf2 KO muscle. Mitochondrial reactive oxygen species production per oxygen consumed was elevated in aged Nrf2 KO mice. There was no effect of Nrf2 KO on muscle mass normalized to body weight. These results suggest that Nrf2 deficiency exacerbates age-related mitochondrial oxidative stress but does not affect the decline of respiratory function in skeletal muscle.

Topics: Age Factors; Aging; Aldehydes; Animals; Cell Respiration; Electron Transport Complex IV; GTP Phosphohydrolases; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Muscle; Mitochondrial Dynamics; Muscle, Skeletal; NF-E2-Related Factor 2; Oxidative Stress; Protein Carbonylation; Sarcopenia