Mechanisms of fibroadipogenic progenitor cell regulation of skeletal muscle recovery after injury and responses to whole-body weight loss

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Trustees of the University of Pennsylvania $100,228 on December 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847).

The award funds research on fibroadipogenic progenitor cell regulation of skeletal muscle recovery after injury and metabolic responses to whole-body weight loss. The research addresses how fibroadipogenic progenitor cells—tissue-resident fibroblast-like cells that support muscle mass maintenance—shift their function during weight loss, and how this shift affects differential responses to exercise-induced skeletal muscle injury. The work studies fibroadipogenic progenitor cells from lean, obese, and weight-loss conditions to understand how whole-body metabolic state informs these cells' capacity to support myogenesis and muscle recovery.

Performance runs from December 1, 2026, through May 31, 2028, at the University of Pennsylvania in Philadelphia, Pennsylvania. This is a project grant, the primary mechanism for investigator-initiated biomedical research under NIDDK's extramural portfolio.

Abstract

Obesity is a global epidemic, and the recent surge in popularity of GLP-1 agonist drugs for weight loss to combat this problem has shed light on the effects of whole-body weight loss on skeletal muscle. FAT mass loss is typically accompanied by lean mass loss, and many patients are encouraged to engage in exercise to counteract this problem. Obesity is associated with a greater risk for exercise-induced injury, but the differences in response to injury and prognosis for recovery between lean, obese, and weight-loss individuals is not well understood. Skeletal muscle is uniquely capable of regeneration in the adult, during which muscle progenitor satellite cells (muscs) fuse into new contractile myofibers. This process is dependent on fibroadipogenic progenitor cells (faps), a tissue-resident fibroblast-like cell type that plays a supportive role in maintaining muscle mass even under homeostatic conditions. Preliminary work has identified that faps adopt a distinct transcriptional identity to become "activated" and respond to injury. However, the precise mechanism by which faps promote skeletal muscle recovery after injury is not known. Another unanswered question regarding faps is how a supportive cell type under homeostasis undergoes a shift to become permissive of tissue atrophy loss during weight loss, and how this shift might dictate differential responses to skeletal muscle injury. This has led to the hypothesis that faps derived from tissues of animals that have lost weight have a cell-intrinsic reduced capacity to support myogenesis that is also observable at the tissue level. This proposal seeks to address these questions by studying faps in lean, obese, and weight-loss faps to understand how the whole-body metabolic state might inform these cells' responses to a physiologically relevant, exercise-induced injury. Furthermore, this proposal will take advantage of innovative new mouse models to delineate the mechanism by which faps influence the regenerating tissue microenvironment and sustain muscle health. Crucially, the applicant for this fellowship, natalie moore, will acquire significant research and scientific training as a student in the university of pennsylvania's biomedical graduate studies program. Her training plan, developed in collaboration with her sponsor, DR. David merrick, and CO-sponsor, DR. Patrick seale, will guide her towards achieving these goals and becoming a productive biomedical researcher. She will benefit from the training environment of the university of pennsylvania and the institute for diabetes, obesity, and metabolism, and will carry the skills gained as part of this fellowship with her as she embarks on a career as an innovative and independent scientist.