Ribosome Biogenesis and Skeletal Muscle in Health and Disease

Abstract

Protein synthesis is the predominant process enabling skeletal muscle to adaptively regulate its size. The synthesis of new proteins is regulated by both the capability of the existing protein synthetic machinery - the ribosome - to translate mRNAs, a process termed ‘translational efficiency’; and by the quantity of available ribosomes for translation, a process called ‘translational capacity’. This is primarily defined by ribosome biogenesis. Translational efficiency has been a major focus in muscle research field, however little is known about the role of translational capacity and ribosome biogenesis during regulation of muscle mass. The aim of this thesis is to investigate the role of the ribosome biogenesis during muscle growth and muscle growth impaired conditions. Experimentally, the analyses focused on the expression of the precursor ribosomal RNA (45S pre-rRNA), the rate-limiting step of ribosome biogenesis. Additionally, the upstream pathways leading to the ribosomal DNA transcription were also investigated. The initial studies of this thesis aimed at evaluating whether in healthy subjects, a growth stimulus such as a single bout of resistance exercise (RE) and further repeated RE training (RT) promotes ribosome biogenesis. It was demonstrated that rDNA transcription is upregulated for 2 days following RE. Chronically, RT promoted increase in ribosome RNA content, and more importantly, the increase in rRNA was associated with changes in muscle mass. Following the determination that ribosome biogenesis occurs during muscle growth, the role of ribosome biogenesis during muscle growth impaired conditions such as muscle inflammation, disuse and ageing was also analysed. It was found that ribosome biogenesis was reduced in those conditions, paralleling muscle loss or inability to increase muscle mass. Thus it was established that ribosome biogenesis is an important mechanism regulating muscle mass. Resistance exercise activates pathways associated with ribosome biogenesis resulting in increased pre-rRNA expression. Additionally, muscle inflammation and limb immobilisation impair muscle ribosome biogenesis and reduce rRNA content. Ageing also appears to impair the RE-induced increase in pre-rRNA. Muscle reloading and high doses of whey protein promote ribosome biogenesis in middle-aged and older subjects. Combined, these data demonstrate that ribosome biogenesis may be a rate limiting step of muscle growth.