The Role of Ceramides in Skeletal Muscle

总结 营养过剩和缺乏身体活动会促进神经酰胺等鞘脂的积累，从而阻止神经酰胺的形成 胰岛素信号传导和合成代谢。实施药物或遗传干预措施， 啮齿类动物中的鞘脂水平可预防或逆转一系列令人印象深刻的代谢病理（例如胰岛素 抵抗、糖尿病、脂肪性肝炎、高血压、心肌病和动脉粥样硬化）。阐明本 通过神经酰胺有助于这些疾病的组织特异性机制，我们已经产生了小鼠 允许神经酰胺生物合成所需的酶的条件性、细胞类型限制性消融，或 降解（即丝氨酸棕榈酰转移酶和二氢神经酰胺去饱和酶-1）或降解（即酸 神经酰胺酶）。我们将应用这些工具来剖析控制神经酰胺合成的调节机制， 在骨骼肌中的作用。该项目的目标包括： 使用这些新的小鼠模型来评估肌肉特异性神经酰胺耗竭或 诱导胰岛素敏感性、肌肉生长和基因组/蛋白质组特征， 营养过剩和缺乏活动。 在离体人肌管中应用神经酰胺通量测定以鉴定 影响神经酰胺生物合成速率;以及， 为了确定一类新的二氢神经酰胺去饱和酶-1抑制剂的疗效，我们的首选药物是 神经酰胺合成途径中的靶点，作为改善肌肉胰岛素敏感性的治疗剂， 防止啮齿动物的肌肉损失。 从这些研究中获得的发现可以揭示调节胰岛素的新的营养感应机制 敏感性和肌肉生长。此外，翻译成分可能导致新的药理学作用。 改善肌肉健康的方法。

SUMMARY Overnutrition and physical inactivity promote the accumulation of sphingolipids such as ceramides which block insulin signaling and anabolic metabolism. Implementation of pharmacological or genetic interventions to reduce sphingolipid levels in rodents prevents or reverses an impressive array of metabolic pathologies (e.g. insulin resistance, diabetes, steatohepatitis, hypertension, cardiomyopathy, and atherosclerosis). To elucidate the tissue-specific mechanisms through which ceramides contribute to these diseases, we have produced mice allowing for the conditional, cell-type restricted ablation of enzymes required for ceramide biosynthesis or degradation (i.e. serine palmitoyltransferase and dihydroceramide desaturases-1) or degradation (i.e. acid ceramidase). We will apply these tools to dissect the regulatory mechanisms controlling ceramide synthesis and action in skeletal muscle. Aims of the project include the following:  To use these novel mouse models to evaluate the effect of muscle-specific ceramide depletion or induction on insulin sensitivity, muscle growth, and genomic/proteomic signatures under conditions of overnutrition and inactivity.  To apply a ceramide flux assay in isolated human myotubes to identify the regulatory mechanisms that influence rates of ceramide biosynthesis; and,  To determine the efficacy of a new class of inhibitors of dihydroceramide desaturases-1, our preferred target in the ceramide synthesis pathway, as therapeutics that improve muscle insulin sensitivity and prevent muscle loss in rodents. Findings obtained from these studies could uncover new nutrient-sensing machinery that modulates insulin sensitivity and muscle growth. Moreover, the translational component could lead to new pharmacological approaches for improving muscle health.