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福祉都很重要。骨骼肌的衰弱是由于某些疾病状态、衰老和因疾病-损伤-手术导致的长期不活动所致。这可能会导致失去正常的活动和行动能力，并增加跌倒和事故的发生率，这对医疗保健费用产生了相当大的影响。有一种名为钙调蛋白的蛋白质家族，它与许多影响肌肉功能的因素有关，但它们是如何参与的尚不清楚。钙蛋白酶是一种蛋白酶，即。它们破坏其他蛋白质，并受细胞内钙浓度的调节。当肌肉细胞收缩时，细胞内的钙浓度会急剧增加。在肌肉细胞内，重要的是对钙调蛋白有严格的调节，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，众所周知，与健康的肌肉纤维相比，静息肌肉纤维中的钙浓度会增加。我们认为，由于这一结果，钙痛将受到较少的调控，并将对肌肉造成损害，从而导致这些疾病中出现的肌肉无力。虽然钙化痛与肌肉营养不良相关的症状有关，但它们所起的作用当然还不清楚。我们的研究计划的目标是了解哪些因素会影响：1)钙化蛋白位于何处，以及2)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来自Duchenne肌营养不良症动物模型MDX小鼠的肌肉中进行比较。

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.