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

Sayed, R. K. A.; Lange, A. N.; Paez, H. G.; Hibbert, J. E.; Meinhold, M.; Flynn, C. G. K.; Vergara, M. B. Z.; Dobrzycki, I.; Wrucke, D. J.; Zepeda, C. S.; James, J. J.; Sundberg, C. W.; Hornberger, T.

doi:10.64898/2026.02.16.706166

bioRxiv · 10.64898/2026.02.16.706166

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

Sayed, R. K. A.·Lange, A. N.·Paez, H. G.·Hibbert, J. E.·Meinhold, M.·Flynn, C. G. K.·Vergara, M. B. Z.·Dobrzycki, I.·Wrucke, D. J.·Zepeda, C. S.·James, J. J.·Sundberg, C. W.·Hornberger, T.

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Abstract

BackgroundAging 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. MethodsSkeletal 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. ResultsAging 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%, P < 0.005) and CSA (32%, P < 0.001) in a sex-independent manner, and these effects were associated with radial atrophy of SERCA1-positive fibers (23%, P < 0.05). Ultrastructural analyses revealed that the radial atrophy was driven by a reduction in the number of myofibrils per fiber (23%, P < 0.05) without changes in myofibril CSA. In mice, aging produced similar macro-to-ultrastructural adaptations in various flexor muscles; however, radial atrophy of the highly glycolytic/Type IIb fibers, which are not present in human limb muscles, was also associated with a decrease in the CSA of the myofibrils (9%, P < 0.005). We also determined that disuse led to radial atrophy of SERCA1-positive fibers (24%, P < 0.001), and this was mediated by a decrease in both the number (22%, P < 0.005) and size of the myofibrils (4%, P < 0.05). Notably, the results also revealed that the magnitude of the disuse-induced adaptations was significantly blunted with aging. ConclusionThis 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.

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Sayed, R. K. A., Lange, A. N., Paez, H. G., Hibbert, J. E., Meinhold, M., Flynn, C. G. K., Vergara, M. B. Z., Dobrzycki, I., Wrucke, D. J., Zepeda, C. S., James, J. J., Sundberg, C. W., Hornberger, T.. 2026-02-18. Macroscopic to Ultrastructural Analyses Identify the Loss of Myofibrils as the Primary Mediator of Muscle Fiber Atrophy in Aging and Disuse. https://doi.org/10.64898/2026.02.16.706166

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