Mechanisms of human skeletal muscle protein turnover

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Skeletal muscle represents the largest protein reservoir in the human body. The proteins within skeletal muscle (and other tissues) are constantly and simultaneously being synthesized and degraded. This constant protein turnover provides for an efficient mechanism for removal of damaged proteins and replacement with new proteins. In mature, post-growth, skeletal muscle a number of hormonal, nutritional, and mechanical stimuli are integrated in their regulation of the processes of muscle protein synthesis (MPS) and muscle protein breakdown (MPB). The balance between MPS and MPB is a large determinant of net muscle protein gain and thus, muscle fibre enlargement (hypertrophy) or reduction (atrophy).***My research program has made extensive use of stable isotope metabolic tracers to study the acute regulation of skeletal muscle protein turnover MPS and MPB. We have combined these highly complex measures with measures of signalling protein activation, gene expression, and histochemistry to create an integrated picture of the factors that contribute to the acute regulation of skeletal muscle protein mass in humans. These acute protein turnover studies have also given us some insight into longer-term phenotypic changes in skeletal muscle. We have also made extensive use of loading and unloading, using voluntary resistance exercise or limb immobilization (i.e., casting), paradigms to try and ascertain how skeletal muscles senses load and altered acute and chronic loading affects both MPS and MPB. However, we still lack basic mechanistic regulatory knowledge as to how loading and unloading work to affect changes in MPS and MPB. As well, from a regulatory standpoint, the nutritional triggers associated with stimulating MPS and supressing MPB are relatively understudied. My proposed program of study is aimed at trying to understand the complex mechanisms that are governing both acute and chronic MPS and MPB, ultimately determining gains or losses in skeletal muscle protein mass and metabolic activity. While we have been successful in unravelling some of these mechanisms and in challenging certain entrenched paradigms, a more advanced and integrated knowledge requires that new methods be established, validated and applied to different models. To address these issues, we will make use of recent advances in mass spectrometry, new models of isotopic tracers, `omic' technologies to understand response variation, and we will continue to use various acute and chronic loading and unloading paradigms to try and ascertain how skeletal muscle senses, and responds to, loading states in terms of protein turnover. In the proposed projects we also plan to extend our previous work by studying these molecular bridges between the extracellular matrix, integrin receptors, and myofilaments.***