Molecular Mechanisms of Fiber Type-Specific Skeletal Muscle Dysfunction with Aging

Human aging is accompanied by a loss of skeletal muscle mass (sarcopenia) that is vastly exceeded by the ability to generate power (dynapenia), and the problem is exacerbated by the increased fatigability (activity- induced reduction in power) when older adults perform dynamic exercise. This is an important health care problem because the impaired power generating capacity can result in limited mobility, increased risk of falling, and a reduced quality of life. Despite the clear clinical significance, the cellular and molecular mechanisms underlying the complex aging skeletal muscle phenotype are poorly understood. A key issue contributing to this problem is likely the divergent effects aging has on slow versus fast muscle fiber types. However, despite ~25 years of research, the extent that fiber size (atrophy) versus altered intrinsic contractile function are contributing to contractile dysfunction with aging remains unresolved, and the mechanisms for the divergent effects aging has on slow and fast fibers, particularly fiber power and size, are poorly understood. Thus, the overall objective of this proposal is to discover the molecular mechanisms that mediate fiber type-specific aging in males and females. Our central hypothesis is that the intrinsic contractile function of both fiber types is preserved with aging, and the selective atrophy of the fast fibers coupled with fiber type-specific metabolic changes drive the complex aging phenotype of sarcopenia, dynapenia and increased fatigability. The central hypothesis will be tested by pursuing three aims: (1) quantify proteome changes with fiber type-specific atrophy in older males and females, (2) determine the cross-bridge mechanisms for the fiber type-specific impairments in contractile function of older males and females, and (3) identify the fiber type-specific proteomic profiles that predict whole muscle dysfunction in older males and females. In aim 1, novel approaches for single fiber proteomics and 3D morphology will be performed on the same muscle fibers to reveal how the proteome changes with fiber size. In aim 2, single fiber contractile function will be paired with either 3D morphology or proteomics of the same fibers to reveal if the age-related loss of power is driven primarily by fiber size or altered cross-bridge mechanics and identify the key proteins contributing to age differences in fiber contractile function. In aim 3, we will use machine learning to determine how fiber type-specific single fiber proteomic profiles determine age-related whole muscle dysfunction. The rationale for this research is that measuring pairwise combinations of single muscle fiber 3D morphology, contractile function, and proteomes will reveal mechanisms of fiber type-specific aging. This approach is innovative, because it departs from the status quo by integrating novel analytical approaches by collecting fiber type-specific molecular data with gross biological measurements of single fiber and whole muscle function and morphology, which will likely allow us to answer long standing questions in the field. This contribution will be significant because it is expected to reveal novel therapeutic targets that can be manipulated to treat sarcopenia, dynapenia and fatigability to improve the quality of life in older males and females. Project Number: 1R01AG086469-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Christopher Sundberg (+1 co-PI) | Institution: UNIVERSITY OF WISCONSIN-MADISON, MADISON, WI | Award Amount: $698,690 | Activity Code: R01 | Study Section: Aging Systems and Geriatrics Study Section[ASG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11128032