A novel paradigm of metabolic regulation: acute and chronic redox-circuitry control of energy homeostasis

骨骼肌收缩需要大量的能量，这些能量主要由我们饮食中的碳水化合物和脂肪提供。大部分能量在肌肉细胞内的特殊细胞器中释放，称为线粒体，通过特定的酶途径分解碳水化合物和脂肪。这些酶必须在收缩过程中迅速激活。酶激活的传统解释包括将高能分子，如磷酸盐(磷酸化)添加到酶的特定位置(共价调节)或将收缩过程中产生的小化合物(如代谢物)添加到其他位置(变构调节)。然而，有证据表明，与骨骼肌代谢有关的第三种调节酶形式尚未得到详细研究：氧化还原信号。 氧化还原信号不是通过结合小分子来改变酶的活性，而是从被称为氧化剂的高活性化学物质中传递能量。这些氧化剂中的许多是在肌肉收缩期间或之后从多种来源产生的，包括位于肌肉细胞附近的血管、肌肉细胞本身的细胞质，或者可能在线粒体内，特别是在收缩之后，作为代谢的副产品。这些氧化剂(如超氧化物、过氧化氢等)会改变酶上被称为半胱氨酸的特定氨基酸的能量状态。半胱氨酸是其他细胞类型和疾病(如癌症)中蛋白质的强大调节器，但很少在骨骼肌中被检测到。鉴于收缩和饮食都会产生氧化剂，氧化还原信号很可能是调节许多代谢途径的一种强大但尚未解释的机制。鉴于数以千计的蛋白质含有暴露的半胱氨酸，这种氧化还原模式实际上可能是调节肌肉细胞新陈代谢的主要方法。这项研究建议可能为理解饮食和运动如何调节骨骼肌新陈代谢提供一个“缺失的环节”。这项工作还将培训未来的研究人员先进的分子、生化和生理方法。

Skeletal muscle contraction requires an enormous amount of energy which is supplied mainly through carbohydrates and fats in our diet. Most of this energy is released in special organelles within muscle cells known as mitochondria which break down carbohydrates and fats through specific enzyme pathways. These enzymes must be activated rapidly during contraction. Traditional explanations for enzyme activation include the addition of high-energy molecules, such as phosphates (phosphorylation) to specific sites on enzymes (covalent regulation) or small compounds generated during contraction, such as metabolites, to other sites (allosteric regulation). However, there is evidence for a third form of regulating enzymes which has not been examined in detail with regards to skeletal muscle metabolism: redox signalling. Rather than changing enzyme activity through binding small molecules, redox signalling transfers energy from highly reactive chemicals known as oxidants. Many of these oxidants are produced during or after muscle contraction from multiple sources, including from blood vessels located near muscle cells, the cytoplasm within muscle cells themselves or possibly within the mitochondria, particularly after contraction, as a by-product of metabolism. These oxidants (such as superoxide, hydrogen peroxide, others) change the energy state of specific amino acids known as cysteines on enzymes. Cysteines are powerful regulators of proteins in other cell types and diseases (such as cancer) but have rarely been examined in skeletal muscle. Given that both contraction and diets produce oxidants, it is highly likely that redox-signalling is a powerful yet unexplained mechanism of regulating many metabolic pathways. This redox-paradigm may actually be a predominant method of regulating metabolism in muscle cells given that thousands of proteins contain exposed cysteines. This research proposal may provide a 'missing link' for understanding how diet and exercise regulate metabolism in skeletal muscle. This work will also train future researchers in advanced molecular, biochemical and physiological methods.