‘Developmental programming’, as a consequence of suboptimal in-utero and early environments can be associated with metabolic dysfunction in later life, including 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 reduced frequency of long telomeres (48.5-8.6kb) and increased frequency of short telomeres (4.2-1.3kb) 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), increased xanthine oxidase (XO), p67phox and 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 may 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.
- Received June 16, 2016.
- Accepted August 18, 2016.
- © 2016. Published by The Company of Biologists Ltd
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