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Cited by 162Muscle Physiology and DisordersNutrition and Health in AgingMitochondrial Function and Pathology

Nrf2 deficiency exacerbates frailty and sarcopenia by impairing skeletal muscle mitochondrial biogenesis and dynamics in an age-dependent manner

Huang, Dong-Dong, Fan, Sheng-Dong, Chen, Xi-Yi, Yan, Xia-Lin, Zhang, Xian-Zhong, Ma, Bing-Wei, Yu, Ding-Ye, Xiao, Wen-Yu +2 more·2019·Experimental Gerontology
DOI 10.1016/j.exger.2019.01.022
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Abstract

Aim Mitochondrial dysfunction during aging is a key factor that contributes to sarcopenia. Nuclear factor erythroid 2‐related factor 2 (Nrf2) has been increasingly recognized to regulate mitochondrial function. The present study aimed to investigate the role of Nrf2 in the development of frailty and sarcopenia during aging, and to demonstrate whether Nrf2 contributes to the maintenance of muscle mass and function by regulation of mitochondrial biogenesis and dynamics during the aging process. Methods Young (5–6 months), middle‐aged (11‐13 months), old (20–24 months) Nrf2−/− (knockout, KO) mice and age‐matched wild‐type (WT) C57/BL6 mice were used in this study. Physical function of the mice in the 6 groups was assessed by grip strength test, four paw inverted hanging test, rotarod analysis, open field analysis, and treadmill endurance test. Muscle mass was measured by cross‐sectional area (CSA) of tibialis anterior muscles and gastrocnemius muscle weight. The frailty status of the 25 old WT mice and 23 old KO mice were assessed based on the mouse frailty phenotype assessment. Expression levels of genes involved in mitochondrial biogenesis (nuclear respiratory factor 1 (Nrf1), peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (PGC‐1&agr;), mitochondrial transcription factor A (TFAM)) and mitochondrial dynamics (optic atrophy protein 1 (Opa1), mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and dynamin‐related protein 1 (Drp1)) were measured in the skeletal muscle. SDH staining was performed and mitochondrial DNA (mtDNA) copy number was measured. Transmission electron microscopy was used to measure the mitochondria number and morphology. Results Physical function and muscle mass decreased during aging. The mRNA expression levels of Nrf2 decreased with increasing frailty phenotype scores in the old WT mice. There were minimal differences in the physical function and muscle mass between the WT and KO mice in the young groups, whereas Nrf2 deficiency caused a declined physical function and muscle mass in the middle‐aged and old mice, and exacerbated frailty in the old mice. The decreases of the physical function and muscle mass were accompanied by the reduced expression levels of genes involved in mitochondrial biogenesis and dynamics, as well as a reduction of mitochondrial number, mitochondrial content, mtDNA copy number, and an impaired mitochondria morphology in the skeletal muscle. Conclusion Nrf2 deficiency exacerbated frailty and sarcopenia during aging, at least partially by impairing skeletal muscle mitochondrial biogenesis and dynamics in an age‐dependent manner. HighlightsMuscle mass/function and mitochondrial homeostasis are impaired during aging in mice.Decline of muscle mass/function is linked with mitochondrial dysfunction during aging.Nrf2 deficiency has few effect on frailty/sarcopenia and mitochondria in young mice.Nrf2 deficiency worsens mitochondrial dysfunction, frailty/sarcopenia in older mice.

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  • Mitochondria perform critical functions beyond energy production to maintain homeostasis and function in skeletal myocytes, including regulation of intracellular Ca2+ homeostasis, modulation of cell proliferation, and integration of apoptotic signaling.

    “Emerging evidence suggested that apart from energy production, mitochondria perform other critical functions to maintain homeostasis and function in the skeletal myocytes, including regulation of intracellular Ca2+ homeostasis, modulation of cell proliferation, and integration of apoptotic signaling (17–19).”

    From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [19]

  • NRF2 knockout exacerbates frailty and sarcopenia of mice during aging, accompanied by reduced expression levels of PGC-1α, NRF1, and TFAM, as well as a reduction of mitochondrial content in the skeletal muscle.

    “NRF2 knockout exacerbated frailty and sarcopenia of mice during aging, accompanied by the reduced expression levels of PGC-1α, NRF1, and TFAM, as well as a reduction of mitochondrial content in the skeletal muscle (19).”

    From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [19]

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Authors
Huang, D.-D., Fan, S.-D., Chen, X.-Y., Yan, X.-L., Zhang, X.-Z., Ma, B.-W., Yu, D.-Y., Xiao, W.-Y., Zhuang, C.-L., & Yu, Z.
Affiliations
Tongji University (CN)
Corresponding author
  • Zhuang, Cheng-Le
  • Yu, Zhen
ORCID
Venue
Experimental Gerontology
Publisher
Elsevier BV
Published
2019-05
Volume
119
Pages
61-73
ISSN
0531-5565 (ISSN-L)
DOI
10.1016/j.exger.2019.01.022
OpenAlex
W2912530936
Semantic Scholar
30a9530d162f7d67c52afb41ec686749c7632fec
Cited by
162
References
42
Citations by year
2026: 13 · 2025: 22 · 2024: 31 · 2023: 28 · 2022: 23 · 2021: 23 · 2020: 16 · 2019: 6
FWCI
5.63
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Experimental Gerontology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Science and Technology Commission of Shanghai Municipality (16411954200)
  • Fundamental Research Funds for the Central Universities
  • Shanghai Municipal Health and Family Planning Commission (201640013)
  • National Natural Science Foundation of China (81770884, 81800795)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
Nrf2, sarcopenia, frailty, aging, skeletal muscle, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial dysfunction, Nrf2 knockout mice, PGC-1α, TFAM, OPA1, mitofusins, Drp1, mitochondrial DNA copy number, muscle mass, physical function, age-related decline, mitochondrial morphology, oxidative stress
MeSH terms
Frailty, Aging, Animals, Organelle Biogenesis, Disease Models, Animal, Male, Mice, Inbred C57BL, Mitochondria, Muscle, RNA, Messenger, Mice, Knockout, Muscle, Skeletal, NF-E2-Related Factor 2, Mice, Sarcopenia, Mitochondrial Dynamics

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