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Metformin mitigates the impaired development of skeletal muscle in the offspring of obese mice.

ABSTRACT: Maternal obesity is linked with offspring obesity and type 2 diabetes. Skeletal muscle (SM) insulin resistance is central to the development of diabetes. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is inhibited in SM of fetuses born to obese mothers.The aim of this study was to evaluate the effect of maternal metformin administration on AMPK activity and reversion of adverse changes in offspring SM of obese mice.Female weanling C57BL/6J mice received either control diet (CON, 6 mice) or high-fat diet (HFD; OB, 12 mice) for 8 weeks before mating. After mating, mice continued receiving their respective CON or OB diets. In addition, 6 of those 12 mice fed with fat diet also received metformin administration (2?mg per ml in drinking water) throughout gestation and lactation (MET). After weaning at postnatal 21 days, offspring were fed a HFD to mimic a postnatal obesogenic environment until necropsy.Mothers receiving the fat diet developed obesity. OB offspring showed higher adiposity than CON and MET offspring. AMPK phosphorylation was lower in SM of OB offspring. ?-Catenin and myogenic regulatory factors, MyoD and myogenin, were downregulated in OB muscle, whereas the adipogenic marker, peroxisome proliferator-activated receptor-?, was upregulated compared with CON muscle. Metformin administration prevented these changes in OB offspring SM. OB but not MET offspring demonstrated glucose intolerance. Mitochondrial content decreased, and activities of citrate synthase and ?-hydroxyacyl-CoA dehydrogenase also decreased in OB offspring SM, whereas they were recovered in MET offspring SM.Maternal metformin administration improves SM development in OB offspring.

SUBMITTER: Tong JF

PROVIDER: S-EPMC3302133 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Metformin mitigates the impaired development of skeletal muscle in the offspring of obese mice.

Tong J F JF Yan X X Zhao J X JX Zhu M J MJ Nathanielsz P W PW Du M M

Nutrition & diabetes 20110516

<h4>Background</h4>Maternal obesity is linked with offspring obesity and type 2 diabetes. Skeletal muscle (SM) insulin resistance is central to the development of diabetes. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is inhibited in SM of fetuses born to obese mothers.<h4>Objective</h4>The aim of this study was to evaluate the effect of maternal metformin administration on AMPK activity and reversion of adverse changes in offspring SM of obese mice.<h4>Design</h4>Female weanlin ...[more]

PMID: 23449382

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Project description:BackgroundMuscle weakness is a common symptom in numerous diseases and a regularly occurring problem associated with ageing. Prolonged low-frequency force depression (PLFFD) is a form of exercise-induced skeletal muscle weakness observed after exercise. Three different intramuscular mechanisms underlying PLFFD have been identified: decreased sarcoplasmic reticulum Ca2+ release, decreased myofibrillar Ca2+ sensitivity, and myofibrillar dysfunction. We here used these three forms of PLFFD as models to study the effectiveness of a fast skeletal muscle troponin activator, CK-2066260, to mitigate muscle weakness.MethodsExperiments were performed on intact single muscle fibres or fibre bundles from mouse flexor digitorum brevis, which were stimulated with electrical current pulses, while force and the free cytosolic [Ca2+ ] ([Ca2+ ]i ) were measured. PLFFD was induced by three different stimulation protocols: (i) repeated isometric contractions at low intensity (350 ms tetani given every 5 s for 100 contractions); (ii) repeated isometric contractions at high intensity (250 ms tetani given every 0.5 s for 300 contractions); and (iii) repeated eccentric contractions (350 ms tetani with 20% length increase given every 20 s for 10 contractions). The extent and cause of PLFFD were assessed by comparing the force-[Ca2+ ]i relationship at low (30 Hz) and high (120 Hz) stimulation frequencies before (control) and 30 min after induction of PLFFD, and after an additional 5 min of rest in the presence of CK-2066260 (10 μM).ResultsProlonged low-frequency force depression following low-intensity and high-intensity fatiguing contractions was predominantly due to decreased sarcoplasmic reticulum Ca2+ release and decreased myofibrillar Ca2+ sensitivity, respectively. CK-2066260 exposure resulted in marked increases in 30 Hz force from 52 ± 16% to 151 ± 13% and from 6 ± 4% to 98 ± 40% of controls with low-intensity and high-intensity contractions, respectively. Following repeated eccentric contractions, PLFFD was mainly due to myofibrillar dysfunction, and it was not fully reversed by CK-2066260 with 30 Hz force increasing from 48 ± 8% to 76 ± 6% of the control.ConclusionsThe fast skeletal muscle troponin activator CK-2066260 effectively mitigates muscle weakness, especially when it is caused by impaired activation of the myofibrillar contractile machinery due to either decreased sarcoplasmic reticulum Ca2+ release or reduced myofibrillar Ca2+ sensitivity.

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Dataset Information

Metformin mitigates the impaired development of skeletal muscle in the offspring of obese mice.

Publications

Metformin mitigates the impaired development of skeletal muscle in the offspring of obese mice.

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