Intramuscular Adipose Tissue Accumulation is a Key Determinant of Limb Function in Peripheral Artery Disease.

Early human evidence such as case series or small samples is exploring possible benefits.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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. 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. 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,

Evidence level

Early human evidence such as case series or small samples is exploring possible benefits.

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