Energy Allocation to Skeletal Muscle After Physical Activity: The Role of Interleukin-6

Abstract

Interleukin-6 (IL-6) is a multifunctional cytokine with disparate and often contradictory effects. A superficial explanation for this functional diversity is that IL-6 is highly context-dependent and performs a different function when secreted as a myokine during physical activity than as a cytokine during the acute phase response to a pathogen. However, this explanation is inadequate to answer the ultimate question of why the same molecule is secreted in these seemingly distinct contexts. To answer this question, we take an evolutionary perspective and hypothesize that short-term energy allocation underlies many of the functions of IL-6. We use myokine IL-6 secretion during physical activity as a model to elaborate this hypothesis. In response to muscular energy deficit, IL-6 is released from contracting muscle to liberate stored somatic energy. At the same time, IL-6 increases energy uptake in the muscle while decreasing non-essential energy uptake in other tissues. In this thesis, we utilize three different experiments to test the hypothesis of short-term energy allocation by myokine IL-6 during physical activity. In Chapter I, we tested whether muscle secretes IL-6 at evolutionarily relevant levels of physical activity. We found that plasma IL-6 increases after two hours of moderately intense walking in urban populations. This suggests that IL-6 secretion during activity was likely present in ancestral populations and could have been selected for to fuel high physical activity levels characteristic of hunter gatherers. In Chapter II, we investigated the prediction that IL-6 signaling during activity impacts how the muscle adapts to long term physical activity. We demonstrated that the muscle transcriptomic response to four weeks of voluntary wheel running is severely blunted in mice that lack functional IL-6 signaling. However, we observed no differences in gross muscle histology between exercised wildtype and IL-6 knockout mice. This may suggest that IL-6 signaling potentiates metabolic rather than histological muscle adaptation to regular physical activity. Finally, in Chapter III, we explicitly tested whether IL-6 signaling allocates energy to muscle after physical activity by measuring the restoration of muscular energy stores during the recovery from a two-hour exercise bout. We found that the storage of intramuscular triglycerides was attenuated with an IL-6R blockade. Furthermore, anti-inflammatory cytokine release was also diminished. However, abrogation of IL-6 signaling did not impact fatty acid lipolysis and mobilization or gluconeogenesis in this exercise context. Additionally, glycogen resynthesis after exercise was unaffected by an IL-6R blockade. Together, the results from this dissertation suggest that IL-6 may be adapted to allocate primarily fatty acids to the muscle to fuel recovery and long-term muscle adaptation.