Phosphorylation In Skeletal Muscle Research Articles

Maternal Metformin Treatment during Gestation and Lactation Improves Skeletal Muscle Development in Offspring of Rat Dams Fed High-Fat Diet.

Maternal high-fat (HF) diet is associated with offspring metabolic disorder. This study intended to determine whether maternal metformin (MT) administration during gestation and lactation prevents the effect of maternal HF diet on offspring’s skeletal muscle (SM) development and metabolism. Pregnant Sprague-Dawley rats were divided into four groups according to maternal diet {CHOW (11.8% fat) or HF (60% fat)} and MT administration {control (CT) or MT (300 mg/kg/day)} during gestation and lactation: CH-CT, CH-MT, HF-CT, HF-MT. All offspring were weaned on CHOW diet. SM was collected at weaning and 18 weeks in offspring. Maternal metformin reduced plasma insulin, leptin, triglyceride and cholesterol levels in male and female offspring. Maternal metformin increased MyoD expression but decreased Ppargc1a, Drp1 and Mfn2 expression in SM of adult male and female offspring. Decreased MRF4 expression in SM, muscle dysfunction and mitochondrial vacuolization were observed in weaned HF-CT males, while maternal metformin normalized them. Maternal metformin increased AMPK phosphorylation and decreased 4E-BP1 phosphorylation in SM of male and female offspring. Our data demonstrate that maternal metformin during gestation and lactation can potentially overcome the negative effects of perinatal exposure to HF diet in offspring, by altering their myogenesis, mitochondrial biogenesis and dynamics through AMPK/mTOR pathways in SM.

Hydroxytyrosol modifies skeletal muscle GLUT4/AKT/Rac1 axis in trained rats.

Training induces a number of healthy effects including a rise in skeletal muscle (SKM) glucose uptake. These adaptations are at least in part due to the reactive oxygen species produced within SKM, which is in agreement with the notion that antioxidant supplementation blunts some training-induced adaptations. Here, we tested whether hydroxytyrosol (HT), the main polyphenol of olive oil, would modify the molecular regulators of glucose uptake when HT is supplemented during exercise. Rats were included into sedentary and exercised (EXE) groups. EXE group was further divided into a group consuming a low HT dose (0.31 mg·kg·d; EXElow), a moderate HT dose (4.61 mg·kg·d; EXEmid), and a control group (EXE). EXE raised glucose transporter type 4 (GLUT4) protein content, Ras-related C3 botulinum toxin substrate 1 (Rac1) activity, andprotein kinase b (AKT) phosphorylation in SKM. Furthermore, EXElow blunted GLUT4 protein content and AKT phosphorylation while EXEmid showed a downregulation of the GLUT4/AKT/Rac1 axis. Hence, a low-to-moderate dose of HT, when it is supplemented as an isolated compound, might alter the beneficial effect of training on basal AKT phosphorylation and Rac1 activity in rats.

Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance.

Background/ObjectivesLimited numbers of studies demonstrated obesity-induced macrophage infiltration in skeletal muscle (SM), but dynamics of immune cell accumulation and contribution of T cells to SM insulin resistance are understudied.Subjects/MethodsT cells and macrophage markers were examined in SM of obese humans by RT-PCR. Mice were fed high-fat diet (HFD) for 2–24 weeks, and time course of macrophage and T cell accumulation was assessed by flow cytometry and quantitative RT-PCR. Extramyocellular adipose tissue (EMAT) was quantified by high-resolution micro-CT, and correlation to T cell number in SM was examined. CD11a−/− mice and C57BL/6 mice were treated with CD11a-neutralizing antibody to determine the role of CD11a in T cell accumulation in SM. To investigate the involvement JAK/STAT, the major pathway for T helper I (TH1) cytokine IFNγ? in SM and adipose tissue inflammation and insulin resistance, mice were treated with a JAK1/JAK2 inhibitor, baricitinib.ResultsMacrophage and T cells markers were upregulated in SM of obese compared with lean humans. SM of obese mice had higher expression of inflammatory cytokines, with macrophages increasing by 2 weeks on HFD and T cells increasing by 8 weeks. The immune cells were localized in EMAT. Micro-CT revealed that EMAT expansion in obese mice correlated with T cell infiltration and insulin resistance. Deficiency or neutralization of CD11a reduced T cell accumulation in SM of obese mice. T cells polarized into a proinflammatory TH1 phenotype, with increased STAT1 phosphorylation in SM of obese mice. In vivo inhibition of JAK/STAT pathway with baricitinib reduced T cell numbers and activation markers in SM and adipose tissue and improved insulin resistance in obese mice.ConclusionsObesity-induced expansion of EMAT in SM was associated with accumulation and proinflammatory polarization of T cells, which may regulate SM metabolic functions through paracrine mechanisms. Obesity-associated SM “adiposopathy” may thus play an important role in development of insulin resistance and inflammation.

Metabolic effects of mitochondrial uncoupling in murine skeletal muscle: Essential role of AMP-activated protein kinase in metabolic improvements of UCP1-transgenic mice?

Background and aim: Altering the efficiency of mitochondrial respiration may represent an attractive target for the treatment of obesity as well as related disorders. Transgenic (UCP1-TG) mice with ectopic expression of UCP1 in skeletal muscle (SM) show a phenotype of increased energy expenditure and improved glucose tolerance counteracting most of the detrimental effects of high fat diet. We could show an increased AMPK phosphorylation in SM of UCP1-TG mice, likely due to the energy depletion through uncoupling by UCP1. However, the full molecular mechanisms leading to the ameliorated metabolic phenotype of UCP1-TG mice are still not known. The aim of this study was to investigate the potential role of skeletal muscle AMPK activation in the healthy metabolic phenotype of UCP1-TG mice.