Satoshi Fujita

Insulin resistance of muscle protein metabolism in aging.

A reduced response of older skeletal muscle to anabolic stimuli may contribute to the development of sarcopenia. We hypothesized that muscle proteins are resistant to the anabolic action of insulin in the elderly. We examined the effects of hyperinsulinemia on muscle protein metabolism in young (25±2 year) and older (68±1 year) healthy subjects using stable isotope tracer techniques. Leg blood flow was higher in the young at baseline and increased during hyperinsulinemia, whereas it did not change in the elderly. Glucose concentrations and muscle uptake were not different between groups at baseline and during hyperinsulinemia. Leg phenylalanine net balance was not different at baseline and significantly increased in both groups with hyperinsulinemia (P<0.05) but to a greater extent in the young (P<0.05). Muscle protein synthesis increased only in the young during hyperinsulinemia. Muscle protein breakdown did not significantly change in either group, although it tended to decrease in the elderly. Changes in muscle protein synthesis were correlated with changes in leg amino acid delivery (R=0.89; P=0.0001) and blood flow (R=0.90; P<0.0001). In conclusion, skeletal muscle protein synthesis is resistant to the anabolic action of insulin in older subjects, which may be an important contributor to the development of sarcopenia.

Aerobic Exercise Overcomes the Age-Related Insulin Resistance of Muscle Protein Metabolism by Improving Endothelial Function and Akt/Mammalian Target of Rapamycin Signaling

Muscle protein metabolism is resistant to insulins anabolic effect in healthy older subjects. This is associated with reduced insulin vasodilation. We hypothesized that aerobic exercise restores muscle protein anabolism in response to insulin by improving vasodilation in older subjects. We measured blood flow, endothelin-1, Akt/mammalian target of rapamycin (mTOR) signaling, and muscle protein kinetics in response to physiological local hyperinsulinemia in two groups of older subjects following a bout of aerobic exercise (EX group: aged 70 ± 2 years; 45-min treadmill walk, 70% heart rate max) or rest (CTRL group: aged 68 ± 1 years). Baseline endothelin-1 was lower and blood flow tended to be higher in the EX group, but protein kinetics was not different between groups. Insulin decreased endothelin-1 (P < 0.05) in both groups, but endothelin-1 remained higher in the CTRL group (P < 0.05) and blood flow increased only in the EX group (EX group: 3.8 ± 0.7 to 5.3 ± 0.8; CTRL group: 2.5 ± 0.2 to 2.6 ± 0.2 ml · min−1 · 100 ml leg−1). Insulin improved Akt phosphorylation in the EX group and increased mTOR/S6 kinase 1 phosphorylation and muscle protein synthesis (EX group: 49 ± 11 to 89 ± 23; CTRL group: 58 ± 8 to 57 ± 12 nmol · min−1 · 100 ml leg−1) in the EX group only (P < 0.05). Because breakdown did not change, net muscle protein balance became positive only in the EX group (P < 0.05). In conclusion, a bout of aerobic exercise restores the anabolic response of muscle proteins to insulin by improving endothelial function and Akt/mTOR signaling in older subjects.

Muscle tissue changes with aging.

Purpose of reviewThis review article focuses on the changes that occur in muscle with age, specifically the involuntary loss of muscle mass, strength and function, termed sarcopenia. Particular emphasis is given to the metabolic alterations that characterize sarcopenia, and to the potentially treatable causes of this condition, including age-related endocrine and nutritional changes, and inactivity. Recent findingsRecent data reported include those regarding the potential role of insulin resistance in the development of sarcopenia, the potential role of androgens and growth hormone in the treatment of this condition, the usefulness of exercise including both resistance and aerobic training to improve muscle growth and function, and, finally, the possible use of nutritional manipulations to improve muscle mass. SummarySarcopenia is likely a multifactorial condition that impairs physical function and predisposes to disability. It may be prevented or treated with lifestyle interventions and pharmacological treatment. Further long-term investigations are needed, however, to ascertain what type and combinations of interventions are the most efficacious in improving muscle mass and function in older people.

Nutrition and sarcopenia of ageing

Sarcopenia, the loss of muscle mass and function with ageing, is a multifactorial condition that slowly develops over decades and becomes a significant contributor to disability in the older population. Malnutrition and alterations in the muscle anabolic response to nutritional stimuli have been identified as potentially preventable factors that may significantly contribute to sarcopenia. In the present article we review the most recent findings regarding the role of nutritional factors in the development, prevention and treatment of sarcopenia. Specifically, we focus on the nutritional needs of the elderly; the age-related changes in the response of muscle protein metabolism to feeding and to the endogenous hormones released during feeding; and the role played by the splanchnic tissues in the response of muscle proteins to feeding. Finally, we review the issues relative to the potential use of nutritional therapies, including supplementation, for the prevention and treatment of sarcopenia.

Dysregulation of muscle fatty acid metabolism in type 2 diabetes is independent of malonyl-CoA

Aims/hypothesisAn elevated lipid content within skeletal muscle cells is associated with the development of insulin resistance and type 2 diabetes mellitus. We hypothesised that in subjects with type 2 diabetes muscle malonyl-CoA (an inhibitor of fatty acid oxidation) would be elevated at baseline in comparison with control subjects and in particular during physiological hyperinsulinaemia with hyperglycaemia. Thus, fatty acids taken up by muscle would be shunted away from oxidation and towards storage (non-oxidative disposal).Materials and methodsSix control subjects and six subjects with type 2 diabetes were studied after an overnight fast and during a hyperinsulinaemic (0.5xa0mU kg−1 min−1), hyperglycaemic clamp (with concurrent intralipid and heparin infusions) designed to increase muscle malonyl-CoA and inhibit fat oxidation. We used stable isotope methods, femoral arterial and venous catheterisation, and performed muscle biopsies to measure palmitate kinetics across the leg and muscle malonyl-CoA.ResultsBasal muscle malonyl-CoA concentrations were similar in control and type 2 diabetic subjects and increased (p<0.05) in both groups during the clamp (control, 0.14±0.05 to 0.24±0.05xa0pmol/mg; type 2 diabetes, 0.09±0.01 to 0.20±0.02xa0pmol/mg). Basal palmitate oxidation across the leg was not different between groups at baseline and decreased in both groups during the clamp (p<0.05). Palmitate uptake and non-oxidative disposal were significantly greater in the type 2 diabetic subjects at baseline and during the clamp (p<0.05).Conclusions/interpretationContrary to our hypothesis, the dysregulation of muscle fatty acid metabolism in type 2 diabetes is independent of muscle malonyl-CoA. However, elevated fatty acid uptake in type 2 diabetes may be a key contributing factor to the increase in fatty acids being shunted towards storage within muscle.