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

ABSTRACT: This study aims to explore the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) deficiency on skeletal muscle autophagy and the development of sarcopenia. LC3b, P62, Bnip3, Lamp-1, and AMPK protein levels were measured in muscle from young, middle-aged, old Nrf2-/- (knockout, KO) mice and age-matched wild-type (WT) C57/BL6 mice. Autophagy flux was measured in young WT, young KO, old WT, old KO mice, using colchicine as autophagy inhibitor. There was a trend of higher accumulation of LC3b-II, P62, Bnip3, Lamp-1 induced by colchicine in old WT mice compared with young WT mice. Colchicine induced a significantly higher accumulation of LC3b-II, P62, Bnip3, Lamp-1 in KO mice compared with WT mice, both in the young and old groups. AMPK and reactive oxygen species (ROS) were unregulated following Nrf2 KO and increasing age, which was consistent with the increasing trend of autophagy flux following Nrf2 KO and increasing age. Nrf2 KO and increasing age caused decreased cross-sectional area of extensor digitorum longus and soleus muscles. We concluded that Nrf2 deficiency and increasing age may activate AMPK and ROS signals to cause excessive autophagy activation in skeletal muscle, which can be a potential mechanism for the development of sarcopenia.

SUBMITTER: Huang DD

PROVIDER: S-EPMC7185110 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Huang Dong-Dong DD Yan Xia-Lin XL Fan Sheng-Dong SD Chen Xi-Yi XY Yan Jing-Yi JY Dong Qian-Tong QT Chen Wei-Zhe WZ Liu Na-Xin NX Chen Xiao-Lei XL Yu Zhen Z

Aging 20200403 7

This study aims to explore the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) deficiency on skeletal muscle autophagy and the development of sarcopenia. LC3b, P62, Bnip3, Lamp-1, and AMPK protein levels were measured in muscle from young, middle-aged, old Nrf2-/- (knockout, KO) mice and age-matched wild-type (WT) C57/BL6 mice. Autophagy flux was measured in young WT, young KO, old WT, old KO mice, using colchicine as autophagy inhibitor. There was a trend of higher accumulation of ...[more]

PMID: 32244226

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Project description:ObjectivesThe link between skeletal muscle and heart disease remains intriguing. It is unknown how skeletal muscle may be associated with aspects of myocardial structure and function, particularly in the presence of aging-related sarcopenia. We hypothesize that among aging adults with sarcopenia, alterations in myocardial structure and/or function may exist, resulting in a syndrome of "cardio-sarcopenia."MethodsParticipants derived from a community cohort study underwent same-day bioimpedance body composition analysis that measured skeletal muscle in sites such as the trunk, upper limb, and lower limb, and echocardiography for assessment of myocardial structure and function. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia criteria.ResultsWe studied a total of 378 participants, of whom 88 (23.3%) had sarcopenia. Participants with sarcopenia had smaller left ventricular (LV) sizes (lower LV internal diameter end diastole (4.1 ± .7 vs 4.5 ± .6 cm; P < .0001), lower LV internal diameter end systole (2.3 ± .5 vs 2.5 ± .4 cm; P = .010), lower LV posterior wall end diastole (.7 ± .1 vs .8 ± .1 cm; P = .0036), and lower LV posterior wall end systole (1.4 ± .3 vs 1.5 ± .2 cm; P = .0031). Sarcopenic participants also had lower LV mass (106 ± 35 vs 126 ± 53; P = .0014) and lower left atrial (LA) volume (33 ± 13 vs 36 ± 13; P = .033). Adjusting for age and diabetes mellitus, skeletal muscle mass was associated with LV diameter (β = .06; 95% confidence interval [CI] = .03-.09; P < .0001), LV mass (β = 4.04; 95% CI = 1.78-6.29; P = .001), LA diameter (β = .05; 95% CI = .01-.09; P = .007), and LA volume (β = 1.26; 95% CI = .38-2.13; P = .005). A positive linear correlation was observed between LV mass and handgrip strength (r = .25; P < .0001).ConclusionAmong a community sample of older adults with preserved heart function, sarcopenia is associated with reductions in LV and LA sizes. Skeletal muscle mass was independently associated with specific indices of myocardial structure. J Am Geriatr Soc 67:2568-2573, 2019.

Project description:Sarcopenia is an age-related disease characterized by the loss of muscle mass and muscle function. A proper understanding of its pathogenesis and mechanisms may lead to new strategies for diagnosis and treatment of the disease. This study aims to discover the underlying genes, proteins, and pathways associated with sarcopenia in both genders. Integrated analysis of microarray datasets has been performed to identify differentially expressed genes (DEGs) between old and young skeletal muscles. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed to uncover the functions of the DEGs. Moreover, a protein-protein interaction (PPI) network was constructed based on the DEGs. We have identified 41,715 DEGs, including 19 downregulated and 41,696 upregulated ones, in men. Among women, 3,015 DEGs have been found, with 2,874 of them being upregulated and 141 downregulated genes. Among the top up-regulated and downregulated genes, the ribosome biogenesis genes and genes involved in lipid storage may be closely related to aging muscles in men and women respectively. Also, the DEGs were enriched in the pathways including those of ribosome and Peroxisome proliferator-activated receptor (PPAR) in men and women, respectively. In the PPI network, Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1), Cullin 3 (CUL3) and P53 have been identified as significant hub proteins in both genders. Using the integrated analysis of multiple gene expression profiles, we propose that the ribosome biogenesis genes and those involved in lipid storage would be promising markers for sarcopenia in men and women, respectively. In the reconstructed PPI network, neurotrophic factors expressed in skeletal muscle are essential for motoneuron survival and muscle fiber innervation during development. Cullin E3 ubiquitin ligase (Cul3) is an important component of the ubiquitin-proteasome system-it regulates the proteolysis. P53 is recognized as a central regulator of the cell cycle and apoptosis. These proteins, which have been identified as the most significant hubs, may be involved in aging muscle and sarcopenia.

Dataset Information

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

Publications

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

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