Mechanisms of human skeletal muscle protein turnover

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Skeletal muscle represents the largest protein reservoir in the human body. Maintenance of skeletal muscle is key for human locomotion and metabolic health. The proteins within skeletal muscle 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 to maintain proteostasis. In adult 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 primary determinant of net muscle protein gain and thus, muscle fibre enlargement (hypertrophy), or net muscle protein loss and a reduction in muscle fibre size (atrophy). The proposed research program is an integrated and systematic study of skeletal muscle in states of increased loading and unloading, to uncover mechanisms regulating muscle mass gain and loss. We make extensive use of stable isotope metabolic tracers to study the regulation of skeletal muscle protein turnover. We combine these complex measures, which only a handful of labs worldwide can make, with measures of signalling protein activation, transcriptomic gene expression, and histochemistry. Thus, we obtain an integrated picture of the factors that contribute to the acute regulation of MPS and MPB. These acute regulatory studies have also given us mechanistic insight into longer-term phenotypic changes in skeletal muscle, which we will also study. We have developed a new method that, combined with dynamic proteomic analysis, yields unparalleled insight into mechanisms regulating muscle protein turnover. We make extensive use of loading and unloading models, using voluntary resistance exercise or limb immobilization paradigms, to try and ascertain how skeletal muscles sense load and alter 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. The proposed program of study is aimed at trying to understand the complex molecular mechanisms that are governing both acute and chronic MPS and MPB, ultimately determining gains or losses in skeletal muscle protein mass. 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 cutting-edge advances in mass spectrometry, new models of isotopic tracers and `omic' technologies to understand response variation to loading an unloading stimuli. Our continuing studies will encourage the development and training of the next generation of Canadian scientists in an equitable, diverse and inclusive environment.