PAI-1’s role in defining the “myospan” of skeletal muscle

By mass, skeletal muscle is the largest human organ, and it is a potent mediator of health and longevity. The inevitable and progressive loss of muscle with advanced age negatively impacts movement and mobility, respiration, thermoregulation, and numerous other physiological parameters. The biological mechanisms that cause age-related changes in skeletal muscle remain poorly understood. PAI-1 is a 43 kDa, secretory protein involved in diverse biological processes including inflammation, cell death, and senescence. PAI-1 also regulates several pathophysiological processes (e.g., metabolic syndrome and fibrosis) and is a major contributor to the multimorbidity of aging. The latter is consistent with gradual systemic accumulation of PAI-1, over time. The impact of elevated PAI-1 on aging skeletal muscle, however, is also largely unknown. Here, we tested the hypothesis that PAI-1 and its homologs are evolutionarily-conserved, negative regulators of muscle function and, thereby, directly contribute to its age-related deterioration. To examine the effects of augmented PAI-1 levels on skeletal muscle function, we evaluated activation and relaxation, kinetics and mechanics, of single myofibrils isolated from mice overexpressing (OE) PAI-1, which developed accelerated vascular aging. Relative to age-matched controls, skeletal myofibrils from 7-mo-old PAI-1 OE animals generated ~40% less maximum force, which was roughly the same as that produced by myofibrils from a 56-mo-old control mouse. Owing to its rapid life cycle, well-developed genetics, and highly-conserved factors that dictate lifespan, Drosophila melanogaster has been used as a model for aging research for > 100 years. We observed a complete loss of flight ability from one through seven weeks of age. Quantitative proteomics of dissected one-, four-, and seven-week-old indirect flight muscle (IFM) fibers revealed a number of proteins and pathways were significantly up-regulated over time, including several PAI-1 homologs, i.e., members of the serine protease inhibitor family (Spn42D). Muscle-specific knockdown of Spn42Da preserved flight ability over seven weeks. Histological analysis revealed intact myocyte structure, whereas both control and wild-type flies displayed age-related morphological deterioration. These results indicate transcriptional repression of Spn42Da mitigates age-associated skeletal muscle degeneration and preserves flight ability. In conclusion, our findings imply that PAI-1 / Spn42Da contributes to age-related pathologies across phyla, and as a key regulator of skeletal muscle function and longevity, PAI-1 inhibition improves the “myospan” to counter age-related deficits in muscle mass, strength, and function. National Institutes of Health (R01HL124091) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.