The temporal control of load-dependent anabolic and catabolic pathways in human extensor muscles

Ruowei, Li (2013) The temporal control of load-dependent anabolic and catabolic pathways in human extensor muscles. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

Skeletal muscle displays a remarkable plasticity to loading and unloading. Such load-dependence is illustrated by the remodelling of metabolic and myofibrillar protein composition. To date the earliest documented molecular adjustments in unloaded human skeletal muscle consists of pre-translational alteration in the expression of factors regulating protein degradation and synthesis and mitochondrial metabolism. In project one I set out to investigate the changes in protein expression in the soleus and vastus lateralis muscle, muscles involved in posture and movement, after three days of unilateral limb suspension. My findings suggest that early unloading alters FAK-pY397 and metavinculin content, and deregulate the expression of factors that set the slow-oxidative phenotype. The underlying mechanisms governing disuse atrophy have not been characterized. Therefore, in the second project I examined muscle fibre morphology and potential factors associated with anabolic signalling as well as markers representative of the catabolic pathways in response to a chronic unloading period of 21 days in humans. Our findings support the proposition based on animal studies that mechanisms responsible for muscle atrophy involve a decrease in protein synthesis accompanied by an increase in protein degradation. It is well known that adjustments in muscle size are driven by changes in the content of myofibrils. However, how such myofibrillar alterations are integrated at the molecular and the architectural level in muscle fibres that undergo adaptive changes has not been resolved. Thus in project 3 I have examined changes in the content of costamere components with increased and reduced loading of human antigravity muscle in relation to changes in muscle size and molecular parameters of muscle size regulation. The findings suggest that load-dependent plasticity of muscle size is integrated through costamere remodelling via a load-regulated process that involves level alterations of FAK and KAK-pY397 concentration.