Effects of negative energy balance on muscle mass regulation

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Skeletal muscle is pivotal to the body’s metabolism. Losses of skeletal muscle mass have been proposed to predict mortality. Oddly, the regulation of muscle mass itself has accrued relatively little attention. A network of neuro-endocrine factors tightly regulates energy balance and fat mass. An analogous neuro-endocrine network likely contributes to the regulation of muscle mass. Intentional weight loss (dieting) invariably leads to muscle mass losses. We hypothesize that intentional weight loss modifies the responsible regulatory neuro-endocrine network. We will analyze changes in muscle mass and function during and after intentional weight loss. We will dissociate effects of negative energy balance and those actions, which result from a modification of body composition. To address these topics, we will perform a randomized controlled weight reduction trial in 60 post-menopausal women. We will study the subjects before, during, and after weight reduction (with stable weight and after weight regain). Phenotyping will include a detailed analysis of potential endocrine parameters involved in the regulation of muscle mass. Detailed metabolic in-vivo characterization including microdialysis, energy balance, clamps, MRI imaging and ex-vivo analysis of human myotubes from each participant using targeted and unbiased technologies, such as expression profiling will be included. These analyses will improve our understanding of the endocrine regulation of muscle mass and may offer novel endocrine or metabolic targets to avoid the well known side effect of muscle mass reduction during weight loss interventions. We raise the provocative notion that short-term dieting (being clinical reality) could be detrimental, since weight regain is not necessarily accompanied by regain of muscle mass. Furthermore, we will examine the mechanisms responsible for any counterproductive effects.