Older adults are at risk to be injured, ill, and hospitalized resulting in physical inactivity-induced muscle atrophy and weakness. Moreover, older adults have an impaired muscle recovery following disuse. Therefore, there exists a need to further understand the cellular mechanisms behind this impaired muscle regrowth with aging. Macrophages are of vital importance during the muscle regrowth following disuse atrophy, however, their role under such conditions in aging skeletal muscle has surprisingly not been previously elucidated. Therefore, using a mouse model of disuse atrophy and regrowth of skeletal muscle, Dr. Reidy and mentoring team have compiled convincing preliminary data demonstrating an impaired muscle regrowth in aging mice and this is accompanied by a blunted macrophage immune response (recruitment and activation of muscle macrophages) in skeletal muscle during muscle recovery. Therefore, I have proposed to conduct an extensive time course of the muscle macrophage response in old and young mice during recovery from disuse (Aim 1) in order to reveal key time points for novel therapeutic intervention. Macrophage immunotherapy and immunomodulation has been successful to improve muscle recovery following ischemia-reperfusion injury and recovery from disuse in young mice. Given the impaired regrowth in aging skeletal muscle and the potential impact of macrophage therapy the goal of Aim 2 is to use macrophage immunotherapy and immunomodulation to restore the regrowth in aging skeletal muscle following disuse. My preliminary data suggested that aging skeletal muscle has impaired macrophage recruitment, and further supported by a decrease in the mRNA expression, of a pivotal chemotactic factor, chemokine (C-C motif) ligand 2 (CCL2). As a follow-up to Aim 2, we will determine if inhibiting macrophage recruitment (CCL2 KO mice) will result in a phenotype characteristic of old mice during recovery from disuse. We plan to use this data to develop a career development award for follow-up mechanistic and parallel human experiments. Additionally, the research project during this fellowship will be tied with various training experiences including new skill acquisition and exposure to aging and metabolism seminars, grant workshops, and interdisciplinary interactions.
Inactivity-induced muscle atrophy, weakness and particularly that of the impaired regrowth presents a severe problem for the aging adult. There exists a need to further understand the cellular mechanisms that explain the impaired age-related muscle regrowth following skeletal muscle atrophy during disuse. This proposal seeks to test muscle macrophages as a mechanism behind the impaired muscle regrowth and also as an exciting new therapy to restore the regrowth in aging skeletal muscle following disuse.
|Reidy, Paul T; McKenzie, Alec I; Mahmassani, Ziad et al. (2018) Skeletal muscle ceramides and relationship with insulin sensitivity after 2 weeks of simulated sedentary behaviour and recovery in healthy older adults. J Physiol 596:5217-5236|