PMID- 37289374 OWN - NLM STAT- MEDLINE DCOM- 20230905 LR - 20240426 IS - 1573-6768 (Electronic) IS - 1389-5729 (Linking) VI - 24 IP - 5 DP - 2023 Oct TI - Long-term detraining reverses the improvement of lifelong exercise on skeletal muscle ferroptosis and inflammation in aging rats: fiber-type dependence of the Keap1/Nrf2 pathway. PG - 753-769 LID - 10.1007/s10522-023-10042-1 [doi] AB - We investigated the effects of lifelong aerobic exercise and 8 months of detraining after 10 months of aerobic training on circulation, skeletal muscle oxidative stress, and inflammation in aging rats. Sprague-Dawley rats were randomly assigned to the control (CON), detraining (DET), and lifelong aerobic training (LAT) groups. The DET and LAT groups began aerobic treadmill exercise at the age of 8 months and stopped training at the 18th and 26th month, respectively; all rats were sacrificed when aged 26 months. Compared with CON, LAT remarkably decreased serum and aged skeletal muscle 4-hydroxynonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. Superoxide dismutase 2(SOD2) levels were higher in the LAT group than in the CON group in skeletal muscle. However, DET remarkably decreased SOD2 protein expression and content in the skeletal muscle and increased malondialdehyde (MDA) level compared with LAT. Compared with LAT, DET remarkably downregulated adiponectin and upregulated tumor necrosis factor alpha (TNF-alpha) expression, while phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and 70-kDa ribosomal protein S6 kinase (P70S6K) protein expression decreased, and that of FoxO1 and muscle atrophy F-box (MAFbX) proteins increased in the quadriceps femoris. Adiponectin and TNF-alpha expression in the soleus muscle did not change between groups, whereas that of AKT, mammalian target of rapamycin (mTOR), and P70S6K was lower in the soleus in the DET group than in that in the LAT group. Compared with that in the LAT group, sestrin1 (SES1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in the DET group was lower, whereas Keap1 mRNA expression was remarkably upregulated in the quadriceps femoris. Interestingly, the protein and mRNA levels of SES1, Nrf2, and Keap1 in soleus muscle did not differ between groups. LAT remarkably upregulated ferritin heavy polypeptide 1(FTH), glutathione peroxidase 4(GPX4), and solute carrier family 7member 11 (SLC7A11) protein expression in the quadriceps femoris and soleus muscles, compared with CON. However, compared with LAT, DET downregulated FTH, GPX4, and SLC7A11 protein expression in the quadriceps femoris and soleus muscles. Long-term detraining during the aging phase reverses the improvement effect of lifelong exercise on oxidative stress, inflammation, ferroptosis, and muscle atrophy in aging skeletal muscle. The quadriceps femoris is more evident than the soleus, which may be related to the different changes in the Keap1/Nrf2 pathway in different skeletal muscles. CI - (c) 2023. The Author(s), under exclusive licence to Springer Nature B.V. FAU - Wang, Zhuang-Zhi AU - Wang ZZ AD - School of Sport Sciences, Nanjing Normal University, Nanjing, 210023, China. FAU - Xu, Hai-Chen AU - Xu HC AD - Department of Rehabilitation, Shanghai Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China. FAU - Zhou, Huan-Xia AU - Zhou HX AD - Department of Rehabilitation, Shanghai Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China. FAU - Zhang, Chen-Kai AU - Zhang CK AD - School of Sport Sciences, Nanjing Normal University, Nanjing, 210023, China. FAU - Li, Bo-Ming AU - Li BM AD - School of Sport Sciences, Nanjing Normal University, Nanjing, 210023, China. FAU - He, Jia-Han AU - He JH AD - School of Sport Sciences, Nanjing Normal University, Nanjing, 210023, China. FAU - Ni, Pin-Shi AU - Ni PS AD - School of Sport Sciences, Nanjing Normal University, Nanjing, 210023, China. FAU - Yu, Xiao-Ming AU - Yu XM AD - Department of Rehabilitation, Shanghai Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China. FAU - Liu, Yun-Qing AU - Liu YQ AD - Changzhou Sports Hospital, Changzhou, 213022, China. FAU - Li, Fang-Hui AU - Li FH AD - School of Sport Sciences, Nanjing Normal University, Nanjing, 210023, China. 12356@njnu.edu.cn. AD - School of Sport Sciences, Zhaoqing University, Zhaoqing, 222023, China. 12356@njnu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230608 PL - Netherlands TA - Biogerontology JT - Biogerontology JID - 100930043 RN - 0 (NF-E2-Related Factor 2) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - 0 (Kelch-Like ECH-Associated Protein 1) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (Adiponectin) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 0 (RNA, Messenger) SB - IM MH - Rats MH - Animals MH - Rats, Sprague-Dawley MH - *NF-E2-Related Factor 2/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/metabolism MH - Kelch-Like ECH-Associated Protein 1/metabolism MH - *Ferroptosis MH - Tumor Necrosis Factor-alpha/metabolism MH - Adiponectin MH - Phosphatidylinositol 3-Kinases MH - Muscle, Skeletal/physiology MH - Aging MH - Muscular Atrophy/metabolism MH - RNA, Messenger/genetics MH - Inflammation/metabolism MH - Mammals/genetics/metabolism OTO - NOTNLM OT - Aged skeletal muscle OT - Detraining OT - Inflammatory OT - Nrf2 pathway OT - Oxidation stress EDAT- 2023/06/08 13:08 MHDA- 2023/09/05 06:42 CRDT- 2023/06/08 11:12 PHST- 2022/12/11 00:00 [received] PHST- 2023/05/27 00:00 [accepted] PHST- 2023/09/05 06:42 [medline] PHST- 2023/06/08 13:08 [pubmed] PHST- 2023/06/08 11:12 [entrez] AID - 10.1007/s10522-023-10042-1 [pii] AID - 10.1007/s10522-023-10042-1 [doi] PST - ppublish SO - Biogerontology. 2023 Oct;24(5):753-769. doi: 10.1007/s10522-023-10042-1. Epub 2023 Jun 8.