Intramuscular Adipose Tissue Accumulation is a Key Determinant of Limb Function in Peripheral Artery Disease
Abstract
BACKGROUND: Peripheral artery disease (PAD) and its severe form, chronic limb-threatening ischemia (CLTI), significantly impair blood flow to the lower extremities, affecting millions of adults globally. Intramuscular adipose tissue (IMAT) and fibrosis accumulation distinguish patients with CLTI from those with mild PAD, suggesting a role in CLTI pathobiology. However, the functional consequences of IMAT in CLTI remain unclear. METHODS: We compared gastrocnemius muscle samples from patients with PAD/CLTI, those with intermittent claudication, and non-PAD individuals. We analyzed bulk RNA sequencing, proteomic, lipidomic, and single-cell/nucleus RNA sequencing datasets. Additionally, we used murine models of hindlimb ischemia with genetic manipulation of Pparγ, a key adipogenic transcription factor, specifically in fibroadipogenic progenitor cells, the cellular source of IMAT, to modulate IMAT formation and assessed the impact on limb function and pathology. RESULTS: Patients with CLTI exhibited significantly elevated expression of adipogenic genes and proteins in muscle specimens when compared with non-PAD controls. Murine models showed that increasing IMAT formation significantly worsened ischemic limb muscle strength and work output. In contrast, preventing IMAT formation significantly improved ischemic limb muscle strength and work output. These findings were consistent across both male and female mice, although females had a greater tendency to form IMAT compared with male mice. CONCLUSIONS: IMAT accumulation is a key determinant of limb function in PAD/CLTI. Our studies demonstrate that targeting IMAT formation could improve limb function in mice with experimental PAD. Together, these findings suggest that developing strategies to limit or reduce IMAT may improve limb function and walking performance in patients with PAD/CLTI, providing a novel therapeutic avenue to address a critical unmet need.
Article Details
Authors (13)
Victoria R. Palzkill
Departments of Applied Physiology and Kinesiology (V.R.P., D.M., Q.Y., J.C., K.K., C.G.P., T.E.R.), University of Florida, Gainesville, FL.
Divyansha Moparthy
Departments of Applied Physiology and Kinesiology (V.R.P., D.M., Q.Y., J.C., K.K., C.G.P., T.E.R.), University of Florida, Gainesville, FL.
Qingping Yang
Jaewon Choi
Xinyue Liu
Kyoungrae Kim
Departments of Applied Physiology and Kinesiology (V.R.P., D.M., Q.Y., J.C., K.K., C.G.P., T.E.R.), University of Florida, Gainesville, FL.
Ambili B. Appu
Pharmacology and Therapeutics (X.L., A.B.A., D.K.), University of Florida, Gainesville, FL.
Caroline G. Pass
Departments of Applied Physiology and Kinesiology (V.R.P., D.M., Q.Y., J.C., K.K., C.G.P., T.E.R.), University of Florida, Gainesville, FL.
Scott A. Berceli
Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, College of Medicine, University of Florida
Curt D. Sigmund
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI (C.D.S.).
Salvatore T. Scali
Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, College of Medicine, University of Florida
Daniel Kopinke
Pharmacology and Therapeutics (X.L., A.B.A., D.K.), University of Florida, Gainesville, FL.
Terence E. Ryan
Departments of Applied Physiology and Kinesiology (V.R.P., D.M., Q.Y., J.C., K.K., C.G.P., T.E.R.), University of Florida, Gainesville, FL.