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%⅐h ؊1 , and this rate declined to 0.047 ؎ 0.005%⅐h ؊1 by middle age (54 ؎ 1 year; P < 0.01). No further decline in the rate of mitochondrial protein synthesis (0.051 ؎ 0.004%⅐h ؊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.

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. Reported are the reduction of anti-HLA antibody levels and improvement of transplant rates by intravenous immunoglobulin (IVIG) in a randomized, double-blind, placebo-controlled clinical trial. Between 1997 and 2000, a total of 101 adult patients with ESRD who were highly sensitized to HLA antigens (panel reactive antibody [PRA] Ն50% monthly for 3 mo) enrolled onto an NIH-sponsored trial (IG02). Patients received IVIG or placebo. Subjects received IVIG 2 g/kg monthly for 4 mo or an equivalent volume of placebo with additional infusions at 12 and 24 mo after entry if not transplanted. If transplanted, additional infusions were given monthly for 4 mo. Baseline PRA levels were similar in both groups. However, IVIG significantly reduced PRA levels in study subjects compared with placebo. Sixteen IVIG patients (35%) and eight placebo patients (17%) were transplanted. Rejection episodes occurred in 9 of 17 IVIG and 1 of 10 placebo subjects. Seven graft failures occurred (four IVIG, three placebo) among adherent patients with similar 2-yr graft survival rates (80% IVIG, 75% placebo). With a median follow-up of 2 yr after transplant, the viable transplants functioned normally with a mean Ϯ SEM serum creatinine of 1.68 Ϯ 0.28 for IVIG versus 1.28 Ϯ 0.13 mg/dl for placebo. Adverse events rates were similar in both groups. We conclude that IVIG is better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with ESRD. Transplant rates for highly sensitized patients with ESRD awaiting kidney transplants are improved with IVIG therapy.Kidney transplantation is the preferred treatment for patients with ESRD. The benefits are evidenced by prolonged survival and improved quality of life for both children and adults. Despite these well documented benefits, transplant frequency remains lower than desirable as a result of limited organ availability (1,2). In patients with high levels of preformed anti-HLA antibodies (high panel reactive antibody [PRA]; highly sensitized), transplant rates are very low because of the additional immunologic barrier. Approximately 30% of patients on the waiting list are classified as sensitized, meaning they have peak PRA levels Ͼ20%, with about half of these having peak PRA levels Ͼ80%. These antibodies result from exposure to nonself HLA antigens; usually from previous transplants, blood transfusions, or pregnancy. Accordingly, women with ESRD are disproportionately sensitized compared with men.Patel and Terasaki (3) established in 1969 that the presence of anti-donor IgG antibody (positive crossmatch) was a contraindication for kidney transplantation. Accordingly, the higher the PRA, the more difficult it becomes to find an immunologically compatible match. Transplant rates are lower

chronic kidney disease; CST, Canadian Society of Transplantation; CT, computed tomography; DASI, Duke activity status index; DEXA, dual energy X-ray absorptiometry; ESRD, end-stage renal disease; FFP, fried frailty phenotype; HR, hazard ratio; HRQO, health-related quality of life; MCSD, mechanical circulatory support device; MELDNa, model for end-stage liver disease and sodium; MRI, magnetic resonance imaging; SPPB, short physical performance battery.