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The influence of obesity, exercise and diet on age-related skeletal muscle deterioration: New mechanistic insights

Primary Supervisor: Dr Leigh Breen, School of Sport, Exercise and Rehabilitation Sciences

Secondary supervisor: Dr Yu-Chiang Lai

PhD project title: The influence of obesity, exercise and diet on age-related skeletal muscle deterioration: New mechanistic insights

University of Registration: University of Birmingham

Project outline:

Obesity increases the risk of cardiovascular and metabolic diseases and is increasing in prevalence at an alarming rate. On a relative basis, obesity incidence is highest in middle-aged and older adults, which is concerning when one considers the current demographic shift to an ageing population. The incidence of metabolic disease in older age is underscored, in part, by the gradual loss in skeletal muscle mass that occurs from approx. 50 years of age. This age-associated muscle loss is also associated with reduced strength, impaired locomotion/function and increased risk of frailty, falls, and mortality. Importantly, the presence of obesity in older age is thought to exacerbate the rate of skeletal muscle deterioration. As such, understanding the mechanistic links between obesity and muscle wasting in older age will aid the development of interventions to promote ‘high quality’ weight loss (i.e., preferential loss of fat over lean tissue mass) and improved metabolic health in overweight and obese older adults. Such interventions have the potential to reduce the incidence of age-associated comorbidities and extend the number of years lived in good health in our ageing population, with important implications for healthcare expenditure.

Phase 1 (months 0-15)

Whilst the precise mechanisms through which this occurs are yet to be elucidated, evidence from our group and others suggests that obesity-induced systemic inflammation and intramuscular lipid infiltration may impair translational capacity for muscle protein synthesis, particularly in response to normally anabolic stimuli such as exercise contraction and amino acids. Therefore, in the first phase of the proposed PhD project, in vitro cell culture experiments will be performed using serum from young and old lean and obese adults to understand how translational signaling response to various stimuli (i.e., amino acid, contraction). These initial cell culture experiments will then be followed-up in an in vivo human model, in which muscle biopsy samples will be obtained from obese and normal-weight older adults under conditions of nutrient consumption and exercise. Cutting edge methodology will be used to deliver key mechanistic insights into the role of obesity in the regulation of muscle mass in older age, including (but not limited to) western blot, qRT-PCR, immunoflouresence microscopy and stable isotope tracers.

Phase 2 (months 16-36):

Short-term weight loss interventions through energy deficit (i.e., diet and exercise) often lead to a substantial loss of lean tissue mass, which is undesirable in older age given the importance of muscle mass for strength, function and metabolic health. Incorporating a high dietary protein intake during energy deficit, may protect lean tissue mass and promote the referential loss of fat mass during short-term weight loss programme, but this has yet to be investigated in obese older adults. In the second phase of this PhD studentship, obese older adults will complete a short-term diet and exercise intervention, in partnership with the newly developed Gisbert Kapp Exercise Training Facility (due to open in January 2023). Dietary intake will be manipulated to facilitate ‘high quality’ weight loss. Comprehensive tests of physiological function and anthropometrics will be performed before and after the intervention. In addition, muscle biopsy and blood samples will be obtained before and after the intervention and used to determine cellular growth processes using an in vitro cell culture model. Muscle and blood samples will also be analyzed for changes in cellular regulators of muscle protein synthesis and inflammation. We expect that the diet/training intervention will result in substantial weight loss in all obese older adults compared with controls, but with a greater relative proportion of fat mass loss and retention of lean mass through manipulation of the macronutrient composition of the diet.

BBSRC Strategic Research Priority: Integrated Understanding of Health: Ageing

Techniques that will be undertaken during the project:

The proposed project will involve in vitro cell culture, qRT-PCR gene expression of protein translation intermediates, western blot analysis of protein translation intermediates, immunoflouresence microscopy analysis of amino acid transporters and fibre lipid content and morphology, assessment of aerobic fitness, dietary analysis and standardization, immunoassay analysis of systemic inflammation markers.

Contact: Dr Leigh Breen, University of Birmingham