Intramuscular Adipose Tissue Accumulation and Limb Function in Peripheral Artery Disease

10 Mar 20264 min read0 viewsJournal Feed

GIST

Circulation, Ahead of Print. 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.

Clinical Editorial

Context and study aims

The investigation centers on how intramuscular adipose tissue (IMAT) and fibrosis relate to limb dysfunction in peripheral artery disease (PAD) and its severe form, chronic limb-threatening ischemia (CLTI).
The research contrasts skeletal muscle from individuals with PAD/CLTI, those with intermittent claudication, and non-PAD controls to understand IMAT’s functional implications.

Methodological breadth and design

Sex-related differences were explored.

Multimodal human tissue analyses included bulk RNA sequencing, proteomics, lipidomics, and single-cell/nucleus RNA sequencing to characterize adipogenic and related molecular signatures in muscle.
Complementary murine experiments employed hindlimb ischemia with targeted manipulation of Pparγ, a central regulator of adipogenesis, specifically within fibroadipogenic progenitor cells—the presumed cellular source of IMAT.
The primary functional readouts in mice were ischemic limb muscle strength and work output, evaluated in the context of altered IMAT formation.

Key molecular and tissue signals

In CLTI patients, muscle specimens showed higher expression of adipogenic genes and proteins versus non-PAD controls, indicating elevated IMAT-related pathways.
In mice, the degree of IMAT formation correlated with functional outcomes in ischemic limbs.

Functional consequences and directional effects

Augmenting IMAT formation led to worse outcomes in limb strength and work capacity under ischemic conditions.
Conversely, reducing IMAT formation produced improvements in both strength and work output in the ischemic limb model.
Sex differences emerged: both male and female mice showed IMAT-related effects, but females demonstrated a greater propensity for IMAT accumulation.

Uncertainty, limitations, and open questions

The translational applicability to humans remains inferential based on combined human and animal data; explicit clinical outcome data in humans were not reported in this summary.
It is not stated whether specific thresholds of IMAT correlate with functional impairment or whether long-term outcomes beyond immediate muscle function were assessed.