title: Acute Treatment of Resveratrol Alleviates Doxorubicin-Induced Myotoxicity in Aged Skeletal Muscle Through SIRT1-Dependent Mechanisms.
abstract: Study of the exacerbating effects of chemotherapeutics, such as doxorubicin, on the impairment of insulin metabolic signaling in aged skeletal muscle is very limited. Here, we tested the hypothesis that activation of sirtuin 1 deacetylase activity by resveratrol would prevent the disruption of insulin signaling and augmentation of catabolic markers induced by doxorubicin in aged skeletal muscle. Two- and 10-month-old senescence-accelerated mice (prone 8) were randomized to receive saline, doxorubicin, doxorubicin and resveratrol, or a combination of doxorubicin, resveratrol, and sirtinol or EX527. Doxorubicin reduced the sirtuin 1 activity without affecting the phosphorylation levels of IRS1(Ser307), mTOR(Ser2481), Akt(Thr308/Ser473), membranous glucose transporter 4, protein abundance of PDK4, and enzymatic activity of pyruvate dehydrogenase in aged muscles. Intriguingly, resveratrol attenuated the doxorubicin-induced elevations of apoptotic and catabolic markers measured as Bax, caspase 3 activity, apoptotic DNA fragmentation, MuRF-1, ubiquitinated proteins, and proteasomal activity in aged muscles, whereas these beneficial effects were abolished on inhibition of sirtuin 1 by sirtinol or EX527. Markers of insulin signaling were not affected by doxorubicin or resveratrol in the senescent skeletal muscle. Nevertheless, the antiapoptotic and anticatabolic effects of resveratrol in aged skeletal muscle treated with doxorubicin were mediated in a sirtuin 1-dependent signaling manner.
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 852, China.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Sin
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 852, China.
authors.forename: Bjorn T
authors.initials: BT
authors.lastname: Tam
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 852, China.
authors.forename: Angus P
authors.initials: AP
authors.lastname: Yu
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 852, China.
authors.forename: Shea P
authors.initials: SP
authors.lastname: Yip
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 852, China.
authors.forename: Benjamin Y
authors.initials: BY
authors.lastname: Yung
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 852, China.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Chan
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 852, China.
authors.forename: Cesar S
authors.initials: CS
authors.lastname: Wong
authors.affiliation: School of Biomedical Science, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, New Territories, Hong Kong 852, China.
authors.forename: John A
authors.initials: JA
authors.lastname: Rudd
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 852, China. parco.siu@polyu.edu.hk.
authors.forename: Parco M
authors.initials: PM
authors.lastname: Siu
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D066126:Cardiotoxicity / Q000209:etiology / Q000517:prevention & control*; D053148:Caspase 3 / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D011897:Random Allocation; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000187:drug effects* / Q000378:metabolism*; D013194:Staining and Labeling; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D013267:Stilbenes; D004317:Doxorubicin; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Apoptosis; Doxorubicin; Resveratrol; SIRT1