Poor maternal nutrition and accelerated postnatal growth induces an accelerated aging phenotype and oxidative stress in skeletal muscle of male rats

Abstract

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), 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 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.

Maternal obesity has sex‐dependent effects on insulin, glucose and lipid metabolism and the liver transcriptome in young adult rat offspring

“…; Tarry‐Adkins et al . ). The altered metabolic processes demonstrated here in the MO‐F1 such as decreased insulin signalling would support the view that MO shortens offspring lifespan.…”

Maternal obesity accelerates rat offspring metabolic ageing in a sex‐dependent manner

“…; Tarry‐Adkins et al . , ; Vaiserman, ). Most studies on ageing compare only two categorical life course time points.…”

“…Both programming outcomes (Desai et al 2015) and ageing processes (Chahal & Drake, 2007) have been shown to result in metabolic and endocrine dysfunction and increased oxidative stress. This study addresses the urgent need for studies that determine interactions between programming and ageing mechanisms (Rodriguez-Gonzalez et al 2014;Rodriguez-Gonzalez et al 2015;Tarry-Adkins et al 2016Vaiserman, 2018). Most studies on ageing compare only two categorical life course time points.…”

Dynamic changes in morphology, gene expression and microbiome in the jejunum of compensatory‐growth rats induced by protein restriction

“…In addition, Tarryadkins et al . () have shown that oxidative stress and inflammation usually accompany the compensatory growth of rats. Therefore, the elevated expression of Tnf‐α in the jejunum of rats in the LN group indicated chronic inflammation as a cost of the rapid growth rate.…”