It is estimated that 15% of adults aged 60-70 years, and up to 50% of adults aged 80 years and older are affected by sarcopenia?the age related loss of muscle mass and function. A disruption of the homeostatic balance between periods of muscle protein breakdown (predominant during fasting) and muscle protein synthesis (predominant following nutrient ingestion) can result in the loss of muscle mass over time. In particular, research suggests that an inability of muscle to fully respond to the anabolic influence of nutrient intake may contribute significantly to age-related muscle loss. This anabolic resistance is likely influenced by increased age-related inflammation. There is evidence in cell line and animal models that increased levels of the inflammatory cytokine, tumor necrosis factor-? (TNF?) impairs the molecular pathways that initiate muscle protein synthesis (i.e. mammalian target of rapamycin, mTOR signaling), and can accelerate muscle protein breakdown. Obesity, and sedentary lifestyle have been linked to increased TNF? expression, and thus may partially explain impaired muscle protein balance in older adults. The objectives of this AREA(R15) proposal are to 1) determine if lifestyle modification via weight loss and aerobic exercise can reduce skeletal muscle inflammation and subsequently improve nutrient-stimulated muscle protein synthesis in previously sedentary, obese older adults; and 2) expose undergraduate Kinesiology and Nutrition majors to meritorious research. We have recently published data with undergraduate researchers showing that body composition is associated with elevated skeletal muscle expression of TNF? converting enzyme (TACE). One of the primary actions of TACE is to cleave membrane bound TNF? (mTNF?) to soluble TNF? (sTNF?)?a more mature and bioactive form of TNF?. Both TACE and sTNF? are known to be elevated in a number of clinical conditions, including heart disease, cancer, arthritis, and diabetes. Based on these data, we feel that TACE may represent an important and potentially modifiable (via weight loss and aerobic conditioning) regulator of skeletal muscle inflammation in humans. There are currently no data on the associations among skeletal muscle expression of TACE, TNF?, and muscle protein balance. Thus, the focus of this proposal is to determine if 5- 10% diet-induced weight loss and 6-months (3 days per week) of aerobic exercise training can influence: 1) TACE and TNF? expression in skeletal muscle; and 2) improve molecular indices of muscle protein breakdown and nutrient- stimulated muscle protein synthesis (mTOR signaling) in sedentary, obese older adults. Specifically, 60 sedentary, obese older adults will be randomized to one of the following groups: 1) control group (CON), 2) a diet-induced weight loss group (DIET), 3) an aerobic exercise training group (EX), or 4) a diet-induced weight loss + aerobic exercise training group (DIET + EX). The results of this study will advance our understanding of the connections among skeletal muscle inflammation and muscle protein balance in older adults, and validate TACE as a potentially modifiable target for the prevention and treatment of sarcopenia and other age-related inflammatory diseases, which will contribute to the development of practice-based guidelines for healthcare practitioners.
The proposed research is relevant to public health because TNF? converting enzyme (TACE) may represent a potential linchpin between elevated skeletal muscle inflammation and loss of muscle mass and function in older adults?a condition termed sarcopenia. It is critical that this connection is further explored, and that a concerted effort is made to discover biologically plausible interventions (i.e. weight loss, exercise training) to attenuate skeletal muscle inflammation via TACE or other mechanisms. Such interventions could decrease the incidence of sarcopenia leading to a decreases in 1) falls and fractures; 2) loss of independence in older adults; and 3) associated healthcare costs.
