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Using targeted proteomics to probe Sirtuin 1 (SIRT1) regulatory networks in skeletal muscle

Principal Supervisor: Dr Andrew Philp - School of Sport, Exercise and Rehabilitation Sciences

Co-supervisor: Dr Debbie Cunningham

PhD project title: Using targeted proteomics to probe Sirtuin 1 (SIRT1) regulatory networks in skeletal muscle.

University of Registration: Birmingham

Project outline:

A fundamental cellular process thought to be central in the aetiology of ageing is a decline in mitochondrial function, reflecting reduced cellular metabolic capacity across healthspan 1. Critically, environmental factors such as inactivity and poor nutrition appear to exacerbate this rate of decline 1, with strong evidence suggesting that mitochondrial dysfunction is closely associated with the progression of chronic diseases such as obesity, insulin resistance, type 2 diabetes and coronary heart disease 2. Therefore, understanding age-associated mitochondrial decline at the cellular level, and developing strategies aimed at boosting residual mitochondrial capacity holds tremendous therapeutic potential.

A candidate protein, implicated in maintaining mitochondrial function during ageing is the class III NAD+-dependent protein deacetylase, sirtuin 1 (SIRT1). SIRT1 is known to be activated in target tissues by increased NAD+ concentrations 3 making it highly sensitive to exercise and nutrition 3. Interest in the health-span promoting effects of SIRT1 has stemmed from initial genetic overexpression studies demonstrating that Sir2 increases the lifespan of yeast, worms and flies 3. This led to the hypothesis that SIRT1 is an evolutionarily conserved longevity gene 3 important in maintaining mitochondrial function.

The Principal hypothesis to be addressed herein is that activation of SIRT1 can increase mitochondrial biogenesis, thus rescuing the mitochondrial decline present during sarcopenia. To study this hypothesis, this project will combine state-of-the-art proteomic approaches; in combination with novel SIRT1 transgenic mouse models to define the SIRT1 proteome in the context of ageing. The ultimate aim of this research is to develop novel nutritional and pharmaceutical approaches targeting SIRT1 activation and/or inhibition, to ultimately improve muscle function and oxidative capacity in elderly individuals.

References: 

  1. M. H. Vendelbo and K. S. Nair, Biochim Biophys Acta, 2011, 1813, 634-644:
  2. R. R. Wolfe, Am J Clin Nutr, 2006, 84, 475 482.
  3. M. C. Haigis and D. A. Sinclair, Annu Rev Pathol, 2010, 5, 253-295

BBSRC Strategic Research Priority: Molecules cells and systems

Techniques that will be undertaken during the project:

  • Mammalian cell culture
  • Adenoviral overexpression and knockdown
  • Cloning, site-directed mutagenesis
  • Cell metabolic profiling (mitochondrial respiration, substrate utilisation)
  • Proteomics
  • Immunoblotting
  • Immunoprecipitation

Contact: Dr Andrew Philp, University of Birmingham