Investigation of the roles of calcium-dependent proteases in muscle damage and disease

肌肉力量对每个人的健康和幸福都很重要。由于某些疾病状态、衰老和疾病-损伤-手术导致的长时间不活动，会发生骨骼肌衰弱。这可能导致丧失正常活动和行动能力，增加福尔斯和事故的发生率，从而对医疗保健费用产生重大影响。有一个称为钙蛋白酶的蛋白质家族，与影响肌肉功能的许多因素有关，但尚不清楚它们是如何参与的。钙蛋白酶是蛋白酶，即。它们会破坏其他蛋白质，并受细胞内钙离子浓度的调节。当肌肉细胞收缩时，其内部的钙浓度会急剧增加。在肌肉细胞内，重要的是对钙蛋白酶进行严格的调节，以避免它们在正常使用过程中被不适当地激活并导致肌肉损伤。在某些疾病状态下，例如肌营养不良症类型，已知静息肌纤维内的钙浓度与健康肌纤维相比增加。我们认为，由于这种情况，钙蛋白酶将受到较少的调节，并将对肌肉造成损害，这有助于在这些疾病中看到的肌肉无力。虽然钙蛋白酶与肌肉营养不良相关的症状有关，但它们所起的作用肯定不清楚。我们研究计划的目的是了解哪些因素影响i）钙蛋白酶的位置，ii）它们在肌肉纤维中何时被激活以及被激活的程度。我们将在健康肌肉和mdx小鼠肌肉中进行比较，mdx小鼠是杜氏肌营养不良症的动物模型。

Muscle strength is important to the health and well-being of everyone. Skeletal muscle weakening occurs as a result of certain disease states, aging and prolonged inactivity due to illness-injury-surgery. This can result in the loss of normal activity and mobility and an increased incidence of falls and accidents, which impact considerably on health care costs. There is a family of proteins called calpains that have been linked to a number of factors affecting muscle function, however it is not known how they are involved. Calpains are proteases, ie. they destroy other proteins, and they are regulated by the concentration of calcium inside a cell. The calcium concentration increases dramatically inside a muscle cell when it contracts. Inside a muscle cell it is important that there is tight regulation of the calpains to avoid them being activated inappropriately during normal use and causing muscle damage. In certain disease states, such as types of muscular dystrophy, it is known that the calcium concentration within resting muscle fibres is increased compared with healthy muscle fibres. We propose that as a consequence of this, the calpains will be less regulated and will cause damage to the muscle, which contributes to the muscle weakness seen in these diseases. Whilst calpains have been implicated with symptoms associated with muscle dystrophies, the role they play is certainly unclear. The objectives of our research proposal are to understand what factors influence i) where the calpains are located and ii) when and how much they are activated, within muscle fibres. We will compare this in healthy muscle and muscle from mdx mice, an animal model of Duchenne muscular dystrophy.