Regulation of macrophage metabolism in aged muscle during recovery

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Abstract Muscle regrowth and function following disuse atrophy in aged muscle is significantly compromised, and this increases the risk for falls, long-term disability and loss of independence. Therapeutic strategies to enhance muscle recovery are non-existent stemming from a poor understanding of cellular mechanism during regrowth in aging muscle. Invasion of muscle macrophages and polarization to pro- and anti-inflammatory states are critical to promote muscle stem cell function and the full resolution of muscle and function following disuse. More recently, macrophage metabolism has been shown to be tightly coupled to the inflammatory state of activated macrophages and regulated by transcription factors such as HIF-1α and accumulation of TCA intermediates such as succinate. Our preliminary data in impaired aged muscle during early recovery supports decreased macrophage succinate and HIF-1α corresponding to a reduced macrophage glycolytic and inflammatory program and functional characteristics. Therefore, using novel mouse genetic and bone marrow transfer experiments, along with chemical approaches and in vitro studies, we will test if succinate and HIF-1α are key regulatory steps for macrophage metabolic and inflammatory activation during regrowth from disuse in aging muscle and if this dysfunction arises from an aged immune system. In Aim 2, we will translate our pre-clinical findings to young and older humans and confirm our hypothesis by extensively characterizing muscle macrophage metabolic and inflammatory functional states in vivo and in vitro during recovery from disuse atrophy. We anticipate that the findings will identify macrophage metabolism as a future target to accelerate the recovery of aged muscle following disuse related events (e.g., surgery, illness).