title: Effects of long-term resveratrol-induced SIRT1 activation on insulin and apoptotic signalling in aged skeletal muscle.
abstract: OBJECTIVE
  Activation of Foxo1 is known to promote apoptosis and disturbances to insulin signalling. However, their modulating roles in aged skeletal muscle are not clear. The present study tested the hypothesis that long-term (i.e. 8 month) resveratrol supplementation would improve physical traits including exercise capacity and basal voluntary activity of aged mice and modulate insulin/apoptotic signalling in aged skeletal muscle. This study also examined whether these resveratrol-associated alterations would involve orchestration of the SIRT1-Foxo1 signalling axis.
  
  
  METHODS
  Two-month-old SAMP8 mice were randomly assigned to young, aged and aged with resveratrol treatment (AR) groups. The AR mice were supplemented with 4.9 mg(-1) kg(-1) day(-1) resveratrol for 8 months. All animals were subject to endurance capacity test and voluntary motor behaviour assessment. The lateral gastrocnemius muscle tissues were harvested for further analyses.
  
  
  RESULTS
  Long-term resveratrol treatment significantly alleviated the age-associated reductions in exercise capacity and voluntary motor behaviour. The protein content, but not the deacetylase activity of SIRT1 was increased with concomitant elevations of p300 acetylase and acetylation of Foxo1 in aged muscle. The aged muscle also manifested signs of impaired insulin signalling including attenuated phosphorylation of Akt, activity of pyruvate dehydrogenase and membrane trafficking of GLUT4 and elevated levels of phosphorylated IRS1 and iNOS and apoptotic activation measured as Bim, p53 and apoptotic DNA fragmentation. Intriguingly, all these age-related adverse changes were mitigated with the activation of SIRT1 deacetylase activity after long-term resveratrol treatment.
  
  
  CONCLUSIONS
  These data suggest that modulation of the SIRT1-Foxo1 axis by long-term resveratrol treatment enhances physical traits and alleviates the unfavourable changes in insulin and apoptotic signalling in aged muscle.
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, 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, 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, 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, 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, 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, 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, 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, China. parco.siu@polyu.edu.hk.
authors.forename: Parco M
authors.initials: PM
authors.lastname: Siu
mesh_terms: D000375:Aging; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010807:Physical Endurance / Q000187:drug effects; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000187:drug effects / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D007328:Insulin; D009124:Muscle Proteins; D011768:Pyruvate Dehydrogenase Complex; D013267:Stilbenes; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Ageing; Foxo1; Insulin; Resveratrol; SIRT1; Skeletal muscle