Macroscopic to Ultrastructural Analyses Identify the Loss of Myofibrils as the Primary Mediator of Muscle Fiber Atrophy in Aging and Disuse.

Background: Aging and disuse are two of the most clinically relevant conditions associated with the loss of skeletal muscle mass, yet the ultrastructural adaptations that drive these losses remain poorly defined. In particular, it is unclear whether radial atrophy of muscle fibers is driven by a reduction in the size of the existing myofibrils, and/or the loss of myofibrils. Accordingly, the objective of this study was to define the macro-to-ultrastructural adaptations that mediate aging- and disuse-induced loss of muscle mass. Methods: Skeletal muscle structure was assessed at the macroscopic, microscopic, and ultrastructural levels in humans and mice. In humans, magnetic resonance imaging was used to quantify knee extensor muscle volume and cross-sectional area (CSA) in young (19 - 40 years) and old (65 - 84 years) adults, and vastus lateralis biopsies were analyzed for microscopic and ultrastructural adaptations using immunohistochemistry and fluorescence imaging of myofibrils with image deconvolution (FIM-ID). Parallel studies were performed in young (4 months) and aged (24 months) mice, along with the use of unilateral hindlimb immobilization to model disuse. Results: Aging led to a robust loss of skeletal muscle mass that was mediated by coordinated macro-to-ultrastructural adaptations. In humans, aging reduced knee extensor muscle volume (34%, Conclusion: This study identifies the loss of myofibrils as a central and conserved mediator of the radial atrophy of muscle fibers that occurs in response to disuse and aging, while also highlighting smaller context-dependent contributions that can arise from changes in myofibril size.