Effects of Nrf2 deficiency on mitochondrial oxidative stress in aged skeletal muscle

Abstract

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.

Nrf2 deficiency promotes the increasing trend of autophagy during aging in skeletal muscle: a potential mechanism for the development of sarcopenia

“…Previously, most literature held the opinion that aging results in impaired function of Nrf2 in skeletal muscle [18,27], which was based on studies in other tissues, such as Macaca mulatta vascular endothelial/smooth muscle [28], rat kidney [29], and mice myocardial cells [23]. However, several previous studies have investigated the effect of aging on the expression of Nrf2 and its downstream cytoprotective genes in the skeletal muscle but the results were inconsistent [27,30]. In recent years, increasing studies have recognized that expression of Nrf2 and its downstream genes in the skeletal muscle can be activated by physical exercise [27,31].…”

Quantitative Ultrastructural Morphometry and Gene Expression of mTOR-Related Mitochondriogenesis within Glioblastoma Cells

“…This can be achieved by overexpressing or silencing genes of mitochondriogenesis, or genes required to synthesize the mTORC1 complex as well as specific, step-dependent autophagy and mitophagy genes while measuring the efficacy of gene silencing in these experimental conditions. As a matter of fact, knockdown of NRF2 blocks mitochondriogenesis [ 44 , 45 , 46 ]. Many more studies about genetic manipulation of lysosomal activity are needed.…”

New Insights for Cellular and Molecular Mechanisms of Aging and Aging-Related Diseases: Herbal Medicine as Potential Therapeutic Approach

“…Chen et al [128] found that the upregulation of Nrf2 expression could alleviate oxidative stress and DNA damage and inhibit the p53-p21 p16-rb signaling pathway, thereby slowing cell aging. Nrf2 can regulate mitochondrial biogenesis and kinetics to maintain muscle mass and function, and its deficiency with aging increasingly promotes age-related skeletal muscle mitochondrial dysfunction and muscle atrophy [129,130]. Study also found that Nrf2 activation could inhibit age-related inflammatory responses and oxidative stress and delay the occurrence of aging and age-related diseases [131].…”