The Effect of Very Low Calorie Diet (VLCD) With and Without Concomitant Resistance Exercise Training (RET) or High Intensity Interval Training (HIIT) on Muscle Protein Synthesis (MPS) in Middle-aged Overweight Male.

Recent interest has emerged on the role of hypoenergetic very low calorie diets (VLCD) in managing overweight and obese people with or without type 2 diabetes. However, VLCD results in 20-30% of mass lost as lean body mass (LBM) besides adipose tissue. Since LBM in the form of skeletal muscle plays an important role for maintaining whole-body metabolic health and represents a vast protein store, better understanding of the mechanisms of VLCD induced weight loss is very important. In a recent systematic review, the investigators observed that information on the subject is scarce. Early studies with VLCD, using poor quality protein supplements showed that VLCD was associated with an increased risk of adverse mortality outcome mainly due to cardiac muscle atrophy. Although current VLCDs are safer, concerns regarding preservation of LBM persist. This is because, in middle-aged (and older) people who are already suffering the early stages of sarcopenia at approximately 0.5-1%/y from the age of ~40y, VLCD may result in additional significant muscle mass loss. Low muscle mass, especially in older individuals is associated with increased mortality, dynapenia (reduced muscle function) and numerous metabolic conditions. Exercises remain the most effective means by which to maintain and increase muscle mass through stimulation of muscle protein synthesis (MPS). Although studies have shown that losses of LBM during a VLCD can be attenuated with the inclusion of resistance exercise training (RET) [5], the mechanism by which VLCD (with and without exercise) effects MPS is poorly defined. The investigators also know now that high intensity interval training (HIIT) improves LBM, cardiac and metabolic function, yet no study has clarified the outcome of HIIT with VLCD on MPS and LBM. The investigators will investigate the different effects of VLCD with RET, VLCD with HIIT, and VLCD alone on MPS and overall metabolic function in overweight middle-aged males.

This project aims to investigate the impact of VLCD on MPS, insulin sensitivity, muscle structure and function (strength), cardiopulmonary fitness in overweight and obese middle-aged adults with or without RET or HIIT. The investigators hypothesised that VLCD will impair MPS and slightly reduce muscle thickness and function, and cardiopulmonary fitness, while exercises will improve MPS and muscle structure and function. All group will show overall improve in insulin sensitivity.

This study will involve 36 overweight (and obese) male (BMI 27-50kg/m2) subjects aged 30-60y. Subjects will be randomised into one of 3 groups (12 each) following baseline investigations and prior to starting interventions: 1) VLCD; 2) VLCD + RET; 3) VLCD + HIIT.

Subjects will be excluded if they have evidence of:

• Participation in a formal exercise regime
• Active cardiovascular disease: uncontrolled hypertension (BP > 180/110), angina, heart failure (class III/IV), arrhythmia, right to left cardiac shunt, recent cardiac event
• Cerebrovascular disease: previous stroke, aneurysm (large vessel or intracranial), epilepsy
• Respiratory disease including: pulmonary hypertension, chronic obstructive pulmonary disease (COPD), severe uncontrolled asthma,
• Diabetes mellitus.
• Active inflammatory bowel or renal disease
• Malignancy
• Clotting dysfunction
• Musculoskeletal or neurological disorders
• Family history of early (<55y) death from cardiovascular disease
• Known sensitivity/ allergy to contrast Sonovue
• Any other ongoing acute or significant chronic medical condition that is not mentioned above.
• Weight >120kg -weight limit for dual energy x-ray absorptiometry (DXA) scan All subjects will undergo a full medical screening before being enrolled into the study. This screening will involve measures of height and weight, medical history and physical examination, blood tests (for fasting FBC's, U&E's, LFT's, TFT's, glucose, HbA1C, lipid profiles and coagulation), and ECG. Abnormal screening results will be discussed with the subject and their General Practitioner (GP) will be informed appropriately.