Acute Treatment of Resveratrol Alleviates Doxorubicin-Induced Myotoxicity in Aged Skeletal Muscle Through SIRT1-Dependent Mechanisms

Thomas K. Sin, Bjorn T. Tam, Angus P. Yu, Shea P. Yip, Benjamin Y. Yung, Lawrence W. Chan, Cesar S. Wong, John A. Rudd, Parco M. Siu*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

20 Citations (Scopus)

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 IRS1Ser307 , mTORSer2481 , AktThr308/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.
Original languageEnglish
Pages (from-to)730-739
Number of pages10
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume71
Issue number6
Early online date8 Oct 2015
DOIs
Publication statusPublished - Jun 2016
Externally publishedYes

User-Defined Keywords

  • Apoptosis
  • SIRT1
  • Resveratrol
  • Doxorubicin

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