Murphy - Skeletal muscle biochemistry
Our group studies the various aspects of skeletal muscle biochemistry in health and disease, using exercise and disease models in humans, as well as animal models.
Perturbations in the ability of skeletal muscle to produce force results in muscle weakness and can affect the ability of an individual to live independently, maintain energy homeostasis and recover from periods of muscle disuse. Specifically, in muscle samples, we measure proteins in segments of individual fibres allowing issues with skeletal muscle heterogeneity to be overcome.
We also examine movement of proteins following micro-dissection of fibres, allowing us to quantitatively assess the redistribution of proteins following interventions. Our research aims to understand how changes in protein abundance and/or their movements that occur as a result of exercise, disease and ageing can affect the ability of muscle to produce force and thereby confer strength and stability. Such understandings will contribute to understanding how we can maintain strong muscles for a healthy life.
Ca2+ dependent processes in skeletal muscle
Skeletal muscle function is both tightly regulated and dictated by transient changes in the intracellular calcium concentrations via a process called excitation-contraction coupling. As well as controlling the production of muscle force, calcium can trigger other calcium dependent events including cellular signalling and the activation of calcium dependent proteases, calpains.
Our lab is interested in understanding an array of calcium dependent processes in skeletal muscle. Specific projects include the investigation of calpains, where we aim to help understand their regulation and functional properties in skeletal muscle. Overall, we aim to consider physiologically relevant circumstances. As an example, we use exercise as a manipulation to alter intracellular calcium levels. Exercise can also be used to see how stretching a muscle (i.e. lengthening, or eccentric contractions) can affect the activation of calpains and the abundance and/or movement of their in vivo cellular targets. Of importance, if an individual has an absent or non-functional muscle specific calpain-3, they develop a type of muscular dystrophy (LGMD2A).
Other proteins important for excitation-contraction coupling and of interest to us in both skeletal and cardiac muscle include the ryanodine receptor, the dihydropyridine receptor, the sarcoplasmic reticulum Ca2+-ATPase (SERCA) and calsequestrin (CSQ). In collaboration with Professor Graham Lamb, Department of Physiology, Anatomy and Microbiology at La Trobe University, as well as researchers at Victoria University, we investigate how age, disease and exercise training affect the function and abundance of these proteins.
Glycogen metabolism in health and disease
Glycogen metabolism plays an important role in health and disease, as it provides a storage molecule (granule) for glucose in skeletal muscle. Impairment of glucose metabolism results in diabetes. Glycogen stores are affected by the training status of an individual, their age and their metabolic state. We have an interest in understanding how proteins important for glycogen metabolism and regulation, for example, glycogen related proteins, AMP activated kinase (AMPK) and glucose transporter 4 (GLUT4) are involved in skeletal muscle function, in particular in response to exercise and diseases such as type 2 diabetes.
Importantly, we are trying to understand what the mechanisms are that result in an improvement in this metabolic disease following exercise interventions. Much of the work involves isolation of individual muscle fibres and following the movement of proteins following particular interventions. By understanding how and when the various proteins are associated with the glycogen granule, we aim to provide the necessary information to understand the intricate involvement of glycogen with muscle function.
Mitochondrial regulation in skeletal muscle
Skeletal muscle is a highly metabolic organ, with demands increasing as much as 100-fold during exercise. Mitochondria are often referred to as the powerhouses of the cell, being the primary source of oxidative ATP supply. Mitochondria are differentially abundant in muscles of differing fibre type proportions. There are numerous factors that affect mitochondrial function in skeletal muscle. How any of these are affected by disease is of growing interest to researchers as we attempt to understand the extent of mitochondrial involvement in diseases such as metabolic diseases (e.g. Type II diabetes), neuromuscular diseases (e.g. muscular dystrophy) and ageing.
Given the role of mitochondria in muscle and during exercise, as well as the fibre specific responses to exercise and in mitochondrial abundance and likely function, we explore mitochondrial content, function and/or dynamics in skeletal muscle. Of particular interest are diseases such as Type 2 diabetes and the exploration of any impairments in mitochondrial function in skeletal muscle obtained from old compared with young individuals. Mouse models are sometimes used to further investigate changes seen.