title: Poor maternal nutrition and accelerated postnatal growth induces an accelerated aging phenotype and oxidative stress in skeletal muscle of male rats.
abstract: 'Developmental programming', which occurs as a consequence of suboptimal in utero and early environments, can be associated with metabolic dysfunction in later life, including an increased incidence of cardiovascular disease and type 2 diabetes, and predisposition of older men to sarcopenia. However, the molecular mechanisms underpinning these associations are poorly understood. Many conditions associated with developmental programming are also known to be associated with the aging process. We therefore utilized our well-established rat model of low birth weight and accelerated postnatal catch-up growth (termed 'recuperated') in this study to establish the effects of suboptimal maternal nutrition on age-associated factors in skeletal muscle. We demonstrated accelerated telomere shortening (a robust marker of cellular aging) as evidenced by a reduced frequency of long telomeres (48.5-8.6 kb) and an increased frequency of short telomeres (4.2-1.3 kb) in vastus lateralis muscle from aged recuperated offspring compared to controls. This was associated with increased protein expression of the DNA-damage-repair marker 8-oxoguanine-glycosylase (OGG1) in recuperated offspring. Recuperated animals also demonstrated an oxidative stress phenotype, with decreased citrate synthase activity, increased electron-transport-complex activities of complex I, complex II-III and complex IV (all markers of functional mitochondria), and increased xanthine oxidase (XO), p67phoxand nuclear-factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Recuperated offspring also demonstrated increased antioxidant defense capacity, with increased protein expression of manganese superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD), catalase and heme oxygenase-1 (HO1), all of which are known targets of NF-κB and can be upregulated as a consequence of oxidative stress. Recuperated offspring also had a pro-inflammatory phenotype, as evidenced by increased tumor necrosis factor-α (TNFα) and interleukin-1β (IL1β) protein levels. Taken together, we demonstrate, for the first time to our knowledge, an accelerated aging phenotype in skeletal muscle in the context of developmental programming. These findings may pave the way for suitable interventions in at-risk populations.
authors: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 OQQ, UK janeadkins@googlemail.com.
authors: Jane L
authors: 0000-0001-9569-6132
authors: JL
authors: Tarry-Adkins
authors: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 OQQ, UK.
authors: Denise S
authors: DS
authors: Fernandez-Twinn
authors: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 OQQ, UK.
authors: Jian Hua
authors: JH
authors: Chen
authors: Neurometabolic Unit, National Hospital, University College London, London WC1N 3BG, UK.
authors: Iain P
authors: IP
authors: Hargreaves
authors: Neurometabolic Unit, National Hospital, University College London, London WC1N 3BG, UK.
authors: Viruna
authors: V
authors: Neergheen
authors: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 OQQ, UK.
authors: Catherine E
authors: CE
authors: Aiken
authors: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 OQQ, UK.
authors: Susan E
authors: SE
authors: Ozanne
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D000975:Antioxidants; D015415:Biomarkers / Q000378:metabolism; D004249:DNA Damage; D004032:Diet; D005260:Female; D048788:Growth and Development; D007249:Inflammation / Q000473:pathology; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D017208:Rats, Wistar; D059506:Telomere Shortening
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D016328:NF-kappa B; D016877:Oxidants
keywords: Developmental programming; Mitochondria; Oxidative stress; Skeletal muscle