Our preliminary data implicates chronic inflammation as a factor that may lead to biochemical abnormalities in muscle and attenuate some of the adaptive responses to exercise. The objective of this project is to evaluate a hypothesis that chronic inflammation originating from inflamed adipose tissue triggers inflammatory responses within skeletal muscle, leading to oxidative stress, reduced mitochondrial capacity, compromised muscle quality, functional and metabolic impairments, and attenuated adaptive responses to exercise.
Aim 1 will determine the impact of chronic inflammation on skeletal muscle physiology. Skeletal muscle biochemical and functional parameters will be compared in older adults grouped into quartiles based on a composite systemic inflammatory score. Muscle biopsies will be used to evaluate muscle-specific inflammatory responses (TLR4, NLRP3), mitochondrial function (respiratory capacity, oxidant emissions, coupling efficiency), and the impact on the quality of the muscle proteome (mass spectrometry). Adipose tissue inflammation and abundance of senescent cells will be determined from subcutaneous abdominal adipose tissue biopsies. Functional outcomes will include muscle mass, strength, fatigue, whole-muscle oxidative capacity, and glucose metabolism. Outcomes will be measured again following 24 weeks of placebo or eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) to reduce adipose tissue inflammation.
Aim 2 will determine the impact of chronic inflammation on responsiveness to acute exercise. Responsiveness to a single bout of exercise will be compared across inflammation quartiles. Exercise responsiveness will be determined from the induction of muscle protein synthesis and changes in putative transcriptional and proteomic signals known to regulate exercise adaptations in skeletal muscle. Outcomes will be measured again following 24 weeks of placebo or n3-PUFAs to reduce adipose tissue inflammation. The contribution of the proposed research is expected to be a detailed understanding of the mechanistic links between systemic inflammation, adipose tissue inflammation, and local inflammatory responses within aging muscle. This work will also lead to new insights into the influence of chronic inflammation on biochemical and functional parameters in aging skeletal muscle and responsiveness to acute exercise. The knowledge gained in the proposed study will have a positive impact because ?exercise resistance? represents a significant barrier to the prevention and reversal of disease and disability in humans, and understanding the role of inflammation in skeletal muscle physiology may lead to new approaches to enhance the beneficial adaptations to exercise in populations that stand to benefit most. Discovering new ways to enhance training responses in people, particularly those at risk for sarcopenia and related metabolic disorders, will have significant benefit since exercise non-responders have increased risk for metabolic disease.
The proposed research is relevant to public health because it will have a positive impact on developing new approaches to optimize the therapeutic adaptations to physical activity in older adults. Specifically, the proposed study will provide new fundamental knowledge of how chronic inflammation influences skeletal muscle biochemical and functional parameters as well as responsiveness to acute exercise. The project is relevant to the mission of NIA, NIAMS, NIDDK, and NHLBI because it satisfies a critical need for mechanistic insight into factors that limit exercise responsiveness in humans.