RESUMO
Introduction: A hallmark of aging is poor muscle recovery following disuse atrophy. Efficacious strategies to enhance muscle recovery following disuse atrophy in aging are non-existent. Prior exercise training could result in favorable muscle morphological and cellular adaptations that may promote muscle recovery in aging. Here, we characterized the impact of exercise training on skeletal muscle inflammatory and metabolic profiles and cellular remodeling and function, together with femoral artery reactivity prior to and following recovery from disuse atrophy in aged male mice. We hypothesized that 12 weeks of treadmill training in aged male mice would improve skeletal muscle cellular remodeling at baseline and during recovery from disuse atrophy, resulting in improved muscle regrowth. Methods: Physical performance, ex vivo muscle and vascular function, tissue and organ mass, hindlimb muscle cellular remodeling (macrophage, satellite cell, capillary, myofiber size, and fibrosis), and proteolytic, inflammatory, and metabolic muscle transcripts were evaluated in aged exercise-trained and sedentary mice. Results: We found that at baseline following exercise training (vs. sedentary mice), exercise capacity and physical function increased, fat mass decreased, and endothelial function improved. However, exercise training did not alter tibialis anterior or gastrocnemius muscle transcriptional profile, macrophage, satellite cell, capillarity or collagen content, or myofiber size and only tended to increase tibialis mass during recovery from disuse atrophy. Conclusion: While exercise training in old male mice improved endothelial function, physical performance, and whole-body tissue composition as anticipated, 12 weeks of treadmill training had limited impact on skeletal muscle remodeling at baseline or in response to recovery following disuse atrophy.
RESUMO
Poor recovery of muscle size and strength with aging coincides with a dysregulated macrophage response during the early stages of regrowth. Immunomodulation in the form of ex vivo cytokine (macrophage-colony stimulating factor) or polarized macrophage delivery has been demonstrated to improve skeletal muscle regeneration. However, it is unclear if these macrophage-promoting approaches would be effective to improve skeletal muscle recovery following disuse in aged animals. Here, we isolated bone marrow-derived macrophages from donor mice of different ages under various experimental conditions and polarized them into proinflammatory macrophages. Macrophages were delivered intramuscularly into young adult or aged recipient mice during the early recovery period following a period of hindlimb unloading (HU). Delivery of proinflammatory macrophages from donor young adults or aged mice was sufficient to increase muscle function of aged mice during the recovery period. Moreover, proinflammatory macrophages derived from aged donor mice collected during recovery were similarly able to increase muscle function of aged mice following disuse. In addition to the delivery of macrophages, we showed that the intramuscular injection of the cytokine, macrophage-colony stimulating factor, to the muscle of aged mice following HU was able to increase muscle macrophage content and muscle force production during recovery. Together, these results suggest that macrophage immunomodulation approaches in the form of ex vivo proinflammatory macrophage or macrophage-colony stimulating factor delivery during the early recovery phase following disuse atrophy were sufficient to restore the loss of aged skeletal muscle function.NEW & NOTEWORTHY A single intramuscular administration of polarized macrophages into muscles of aged mice following a bout of disuse atrophy was sufficient to improve functional recover similarly to young adults after disuse atrophy regardless of the age or experimental condition of the donor mice. Additionally, intramuscular delivery of macrophage-colony stimulating factor into aged mice was similarly effective. Targeting macrophage function early during the regrowth phase may be a novel tool to bolster muscle recovery in aging.