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Overcoming the blunted response to food to maximise muscle maintenance in the elderly

Reference	BB/C516779/1
Principal Investigator / Supervisor	Professor Michael Rennie
Co-Investigators / Co-Supervisors	Professor Paul Greenhaff, Professor Ian Macdonald, Dr Kenneth Smith, Dr Henning Wackerhage
Institution	University of Nottingham
Department	Sch of Biomedical Sciences
Funding type	Research
Value (£)	1,213,902
Status	Completed
Type	Research Grant
Start date	01/06/2005
End date	31/08/2011
Duration	75 months

Abstract

We recently discovered that men aged 70 y have rates of muscle protein turnover in the fasted post-absorptive state that are equal to those of 28 y old men, but in the older men the muscle protein synthetic responses to essential amino acids (EAA), delivered orally, are blunted. This finding is important (and likely to reduce diurnal muscle maintenance in older men, predisposing to sarcopenia) because we have also shown that the major anabolic stimulus to muscle protein synthesis (MPS) is EAA ¿ with little effect of insulin (shown by insulin clamp studies). In young subjects, insulin appears to be responsible for approximately 20 per centage of the anabolic response to food entirely through the inhibition of muscle protein breakdown (MPB). We predict that in older subjects there is also a blunting of insulin¿s inhibitory effect on MPB. We suggest the blunting effects on both synthesis and breakdown are due to alterations in sensitivity capacity of nutrient sensors, signalling cascades, and protein synthetic and catabolic machinery. We predict that resistance exercise plus immediate feeding will improve muscle maintenance by overcoming this blunting. We have preliminary evidence of sexual dimorphism of the anabolic responses of musculoskeletal protein synthesis in young men and women (with smaller responses in women to amino acids and exercise) and hypothesize that the deficits will be greater in older women. We have shown that amino acids and exercise are synergistic and additive in stimulating MPS in young men and hypothesize that although this effect is present in older subjects it is diminished, although subject to reinvigoration by exercise training. We will test these hypotheses by carrying out studies of muscle protein turnover (MPS and MPB) in healthy young, middle aged and elderly men and women at rest and after exercise, specifically attempting to uncover predicted alterations in the molecular mechanisms and their susceptibility to beneficial alteration byincreased physical activity (resistance training). We will use our well established techniques for measuring MPS by means of incorporation of 13 C leucine into myofibrillar and sarcoplasmic protein, and for MPB by dilution of d5- phenylalanine, with stable isotope analysis by GC-MS and GC-combustionlRMS. We will attempt to match changes in proteolytic activity measured with d5-Phe dilution with activities of proteolytic enzymes and their expression. We will analyse components of the mTOR and GSK3 signalling pathways (total and phosphorprotein) and of proteolytic pathways by immunoblotting after PAGE, and conduct qRT-PCR to discover the extent of expression of key signalling and proteolytic components. The project should not only provide new knowledge of the responses of the muscle mass to food but also help inform the debate on protein requirements of the ageing population, facilitate the prescription of diet and activity regimes for them and provide a rational evidence based context within which food manufacturers can design prepared dietary food supplements or complete diets of suitable protein energy ratio and protein composition.

Summary

unavailable

Committee	Closed Committee - Agri-food (AF)
Research Topics	Ageing, Diet and Health
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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