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Low birth weight is associated with adiposity, impaired skeletal muscle energetics and weight loss resistance in mice.

ABSTRACT: In utero undernutrition is associated with obesity and insulin resistance, although its effects on skeletal muscle remain poorly defined. Therefore, in the current study we explored the effects of in utero food restriction on muscle energy metabolism in mice.We used an experimental mouse model system of maternal undernutrition during late pregnancy to examine offspring from undernourished dams (U) and control offspring from ad libitum-fed dams (C). Weight loss of 10-week-old offspring on a 4-week 40% calorie-restricted diet was also followed. Experimental approaches included bioenergetic analyses in isolated mitochondria, intact (permeabilized) muscle and at the whole body level.U have increased adiposity and decreased glucose tolerance compared to C. Strikingly, when U are put on a 40% calorie-restricted diet they lose half as much weight as calorie-restricted controls. Mitochondria from muscle overall from U had decreased coupled (state 3) and uncoupled (state 4) respiration and increased maximal respiration compared to C. Mitochondrial yield was lower in U than C. In permeabilized fiber preparations from mixed fiber-type muscle, U had decreased mitochondrial content and decreased adenylate-free leak respiration, fatty acid oxidative capacity and state 3 respiratory capacity through complex I. Fiber maximal oxidative phosphorylation capacity did not differ between U and C but was decreased with calorie restriction.Our results reveal that in utero undernutrition alters metabolic physiology through a profound effect on skeletal muscle energetics and blunts response to a hypocaloric diet in adulthood. We propose that mitochondrial dysfunction links undernutrition in utero with metabolic disease in adulthood.

SUBMITTER: Beauchamp B

PROVIDER: S-EPMC4326251 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Low birth weight is associated with adiposity, impaired skeletal muscle energetics and weight loss resistance in mice.

Beauchamp B B Ghosh S S Dysart M W MW Kanaan G N GN Chu A A Blais A A Rajamanickam K K Tsai E C EC Patti M-E ME Harper M-E ME

International journal of obesity (2005) 20140711 4

<h4>Background</h4>In utero undernutrition is associated with obesity and insulin resistance, although its effects on skeletal muscle remain poorly defined. Therefore, in the current study we explored the effects of in utero food restriction on muscle energy metabolism in mice.<h4>Methods</h4>We used an experimental mouse model system of maternal undernutrition during late pregnancy to examine offspring from undernourished dams (U) and control offspring from ad libitum-fed dams (C). Weight loss ...[more]

PMID: 25091727

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Project description:BackgroundAnthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin.MethodsIn a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy.ResultsTwenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m2, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013).ConclusionsContemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31P-metabolism alongside structural skeletal muscle changes.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT04467411.

Project description:Dysregulated skeletal muscle metabolism (DSMM) is associated with increased inter- and intramuscular fat deposition in low birth weight (L) individuals. The mechanisms behind DSMM in L individuals are not completely understood but decreased muscle mass and shifts in lipid and carbohydrate utilisation may contribute. Previously, we observed lower fat oxidation in a porcine model of low birth weight. To elucidate the biological activities underpinning this difference microfluidic arrays were used to assess mRNA associated with lipid metabolism in longissimus dorsi (LD) and semitendinosus (ST) skeletal muscle samples from thirty-six female L and normal birth weight (N) pigs. Plasma samples were collected from a sub-population to measure metabolite concentrations. Following overnight fasting, skeletal muscle and plasma samples were collected and the association with birth weight, diet and age was assessed. Reduced dietary fat was associated with decreased LD intermuscular fat deposition and beta-oxidation associated mRNA, in both birth weight groups. Lipid uptake and intramuscular fat deposition associated mRNA was reduced in only L pigs. Abundance of ST mRNA associated with lipolysis, lipid synthesis and transport increased in both birth weight groups. Lipid uptake associated mRNA reduced in only L pigs. These changes were associated with decreased plasma L glucose and N triacylglycerol. Post-dietary fat reduction, LD mRNA associated with lipid synthesis and inter- and intramuscular fat deposition increased in L, whilst beta-oxidation associated mRNA remains elevated for longer in N. In the ST, mRNA associated with lipolysis and intramuscular fat deposition increased in both birth weight groups, however this increase was more significant in L pigs and associated with reduced beta-oxidation. Analysis of muscle lipid metabolism associated mRNA revealed that profile shifts are a consequence of birth weight. Whilst, many of the adaptions to diet and age appear to be similar in birth weight groups, the magnitude of response and individual changes underpin the previously observed lower fat oxidation in L pigs.

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Low birth weight is associated with adiposity, impaired skeletal muscle energetics and weight loss resistance in mice.

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Low birth weight is associated with adiposity, impaired skeletal muscle energetics and weight loss resistance in mice.

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