Rooyackers, Olav

A decline in muscle mass and contractile function are prominent features of the sarcopenia of old age. Because myosin heavy chain is an important contractile protein, it was hypothesized that synthesis of this protein decreases in sarcopenia. The fractional synthesis rate of myosin heavy chain was measured simultaneously with rates of mixed muscle and sarcoplasmic proteins from the increment of [13C]leucine in these proteins purified from serial needle biopsy samples taken from 24 subjects (age: from 20 to 92 yr) during a primed continuous infusion ofl-[1-13C]leucine. A decline in synthesis rate of mixed muscle protein ( P < 0.01) and whole body protein ( P < 0.01) was observed from young to middle age with no further change with advancing age. An age-related decline of myosin heavy-chain synthesis rate was also observed ( P < 0.01), with progressive decline occurring from young, through middle, to old age. However, sarcoplasmic protein synthesis did not decline with age. Myosin heavy-chain synthesis rate was correlated with measures of muscle strength ( P < 0.05), circulating insulin-like growth factor I ( P < 0.01), and dehydroepiandrosterone sulfate ( P < 0.05) in men and women and free testosterone levels in men ( P < 0.01). A decline in the synthesis rate of myosin heavy chain implies a decreased ability to remodel this important muscle contractile protein and likely contributes to the declining muscle mass and contractile function in the elderly.

▪ Abstract A continuous turnover of protein (synthesis and breakdown) maintains the functional integrity and quality of skeletal muscle. Hormones are important regulators of this remodeling process. Anabolic hormones stimulate human muscle growth mainly by increasing protein synthesis (growth hormone, insulin-like growth factors, and testosterone) or by decreasing protein breakdown (insulin). Unlike in growing animals, insulin's main anabolic effect on muscle protein in adult humans is an inhibition of protein breakdown. Protein synthesis is stimulated only in the presence of a high amino acid supply. A combination of the stress hormones (glucagon, glucocorticoids, and catecholamines) cause muscle catabolism, but the effects of the individual hormones on human muscle and their mechanisms of action remain to be clearly defined. Although thyroid hormone is essential during growth, both an excess and a deficiency cause muscle wasting by yet unknown mechanisms. A greater understanding of the regulation of human muscle protein metabolism is essential to elucidate mechanisms of muscle wasting.

A progressive decline in muscle performance in the rapidly expanding aging population is causing a dramatic increase in disability and health care costs. A decrease in muscle endurance capacity due to mitochondrial decay likely contributes to this decline in muscle performance. We developed a novel stable isotope technique to measure in vivo rates of mitochondrial protein synthesis in human skeletal muscle using needle biopsy samples and applied this technique to elucidate a potential mechanism for the age-related decline in the mitochondrial content and function of skeletal muscle. The fractional rate of muscle mitochondrial protein synthesis in young humans (24 ± 1 year) was 0.081 ± 0.004%·h −1 , and this rate declined to 0.047 ± 0.005%·h −1 by middle age (54 ± 1 year; P < 0.01). No further decline in the rate of mitochondrial protein synthesis (0.051 ± 0.004%·h −1 ) occurred with advancing age (73 ± 2 years). The mitochondrial synthesis rate was about 95% higher than that of mixed protein in the young, whereas it was approximately 35% higher in the middle-aged and elderly subjects. In addition, decreasing activities of mitochondrial enzymes were observed in muscle homogenates (cytochrome c oxidase and citrate synthase) and in isolated mitochondria (citrate synthase) with increasing age, indicating declines in muscle oxidative capacity and mitochondrial function, respectively. The decrease in the rates of mitochondrial protein synthesis is likely to be responsible for this decline in muscle oxidative capacity and mitochondrial function. These changes in muscle mitochondrial protein metabolism may contribute to the age-related decline in aerobic capacity and muscle performance.