Investigating novel regulators of mTORC1 activation in human skeletal muscle

Hodson, Nathan (2019). Investigating novel regulators of mTORC1 activation in human skeletal muscle. University of Birmingham. Ph.D.

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Abstract

The mechanistic target of rapamycin (mTOR), specifically mTOR complex 1 (mTORC1) is believed to be a central regulator of muscle size, however, the upstream mechanisms which activate this kinase in response to anabolic stimuli remain to be fully elucidated. This thesis therefore aimed to investigate the role of several novel regulators of mTORC1 activity in human skeletal muscle. Chapter 3 displays that mTOR translocation to the cell periphery is mTORC1-specific and is greater following resistance exercise (RE) and protein-carbohydrate (PRO-CHO) feeding compared to feeding alone. In chapter 4 we validate and optimise a immunofluorescent staining protocol to visualise L-Type amino acid transporter 1 (LAT1) in human skeletal muscle, where it was more greatly expressed in fast twitch fibres and localised close to sarcolemma and microvasculature. Chapter 5 investigated the role of vacuolar protein sorting 34 (Vps34), a potential nutrient ‘sensor’, in mTORC1 activation in skeletal muscle. Here, both in vitro and in vivo experimental designs were utilised to display that changes in Vps34 cellular location, rather than kinase activity, may be important for nutrient sensing in skeletal muscle. Finally, chapter 6 reports how mTORC1 activation can occur without alterations in Vps34 protein content, kinase activity or LAT1 fibre type distribution in response to RE and/or PRO-CHO feeding. Overall, this thesis enhanced our understanding of the intricate regulation of mTORC1 activity in human skeletal muscle, identifying new potential mechanisms by which anabolic stimuli may regulate this kinase.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):