Role of Gs-alpha in regulation of skeletal muscle metabolism

我们通过将肌肉重链启动子-cre重组酶转基因小鼠与在gs - α外显子1周围有loxP重组位点的floxed gs - α小鼠重复配对，产生了骨骼肌gs - α缺失小鼠（MGsKO小鼠）。MGsKO小鼠存活正常，无明显生理表型。MGsKO小鼠生长正常，体重和成分正常，食物摄入和能量消耗无变化。这些结果表明，肌肉中gs - α的损失似乎不会影响正常卡路里饮食的全身能量代谢。对高脂肪饮食的研究也没有显示出代谢方面的差异。葡萄糖代谢的研究（基线血清化学、葡萄糖和胰岛素耐量试验、高胰岛素正糖钳研究和孤立肌肉的葡萄糖摄取）表明，尽管MGsKO小鼠的胰岛素分泌正常，并且对胰岛素有低血糖反应，但它们是葡萄糖不耐受的。事实上，对孤立肌肉的研究表明，在最大胰岛素刺激下，基础葡萄糖摄取增加，葡萄糖摄取没有变化，尽管MGsKO小鼠肌肉中胰岛素从基线增加较低。此外，肌糖摄取对AMP类似物AICAR的反应不受影响，表明AMP激酶及其下游途径保持完整。MGsKO骨骼肌明显萎缩，纤维横截面积减少。此外，基于肌球蛋白重链亚型和动力学特性，存在从1型（白色，快速抽搐）到2型（红色，慢抽搐）纤维的转换，即使肌肉线粒体含量和氧化能力降低，pgc -1 α表达减少，pgc -1 α是线粒体氧化的已知转录诱导剂，并转换为1型纤维。因此，在MGsKO小鼠中，纤维类型开关与代谢特性的预期变化之间存在分离。这些小鼠也被证明有助于研究肌钙蛋白加工在心肌中的作用，作为减少-肾上腺素能信号的代偿机制。最近的研究表明，这种向2型肌肉的转变是渐进的，可能是肌肉质量减少的代偿机制，可能模仿衰老和肌肉萎缩疾病的情况。研究正在研究肌肉中Gs信号在适应性产热中的作用。最近的模型证实了骨骼肌中gs - α信号对能量平衡的影响不足。这些模型正在被研究，以检查β -肾上腺素能信号在肌肉中对葡萄糖代谢的作用。在肌肉和脂肪组织中敲除Gs的研究表明，脂肪组织和骨骼肌中Gs信号的丢失会导致慢性寒冷条件下的产热功能受损。

We generated mice with Gs-alpha deficiency in skeletal muscle (MGsKO mice) by repeated matings of muscle heavy chain promoter -cre recombinase transgenic mice with floxed Gs-alpha mice which have loxP recombination sites surrounding Gs-alpha exon 1. MGsKO mice have normal survival and no obvious physical phenotype. MGsKO mice had normal growth and body weight and composition and no changes in food intake and energy expenditure. These results show that loss of Gs-alpha in muscle does not appear to affect whole body energy metabolism on a regular calorie diet. Studies on high fat diet also show no evidence of differences in metabolism. Studies in glucose metabolism (baseline serum chemistries, glucose and insulin tolerance tests, hyperinsulinemic euglycemic clamp studies, and glucose uptake in isolated muscles) show that MGsKO mice are glucose intolerant despite the fact that the mice have normal insulin secretion and hypoglycemic response to administered insulin. In fact studies in isolated muscles show basal glucose uptake to be increased and with no change in glucose uptake in the presence of maximal insulin stimulation, although the increase from baseline with insulin was lower in muscles from MGsKO mice. In addition, muscle glucose uptake in response to the AMP analog AICAR was unaffected, indicating that AMP kinase and its downstream pathways remain intact. Skeletal muscles in MGsKO show significant atrophy with reduced fiber cross-sectional area. In addition, there is a switch in from type 1 (white, fast-twitch) to type 2 (red, slow-twitch) fibers based upon myosin heavy chain subtypes and kinetic properties even though the muscles have reduced mitochondrial content and oxidative capacity and reduced expression of PGC-1alpha, a known transcriptional inducer of mitochondrial oxifation and switch to type 1 fibers. Therefore in MGsKO mice there is a dissociation between the fiber type switch and the expected changes in metabolic properties. These mice have also proven useful to examine the role of troponin processing in cardiac muscle as a compensatory mechanism to reduced beta-adrenergic signaling. More recent studies have suggested that this switch to type 2 muscle is progressive and may be a compensatory mechanism for reduced muscle mass, and may mimic the situation seen in aging and muscle wasting disorders. Studies are ongoing examining the role of Gs signaling in muscle in adaptive thermogenesis. More recent models have confirmed the lack of effect of Gs-alpha signaling in skeletal muscle on energy balance. These models are being studied to examine the role of beta2-adrenergic signaling in muscle on glucose metabolism. Studies knocking out Gs in both muscle and adipose tissue show that loss of Gs signaling in both adipose tissue and skeletal muscle leads to impaired thermogenesis in response to chronic cold conditions.