Highlights
- Chronic limb-threatening ischemia (CLTI) is characterized by a distinct adipogenic and fibrotic muscular phenotype compared to mild peripheral artery disease (PAD).
- The accumulation of intramuscular adipose tissue (IMAT) is negatively correlated with muscle strength and work output in both human subjects and murine models.
- Fibroadipogenic progenitor cells (FAPs) are the cellular source of IMAT in ischemic muscle, and their adipogenic potential is regulated by Pparγ signaling.
- Genetic or pharmacological inhibition of IMAT formation significantly improves limb function, offering a potential non-revascularization strategy for PAD patients.
Background
Peripheral artery disease (PAD) is a pervasive cardiovascular condition affecting over 200 million people worldwide. Characterized by atherosclerotic occlusion of the lower extremity arteries, PAD results in a spectrum of clinical manifestations ranging from asymptomatic disease and intermittent claudication (IC) to chronic limb-threatening ischemia (CLTI). While the primary pathology is vascular, the clinical burden of PAD—particularly impaired walking performance and high rates of limb loss—is largely mediated by the secondary changes that occur within the skeletal muscle of the lower limbs.
In patients with CLTI, the muscle environment undergoes profound remodeling. Chronic hypoxia and repeated cycles of ischemia-reperfusion injury lead to muscle fiber atrophy, mitochondrial dysfunction, and the replacement of contractile tissue with non-contractile elements, specifically collagen (fibrosis) and adipose tissue (myosteatosis). While the presence of intramuscular adipose tissue (IMAT) has been documented in aging, diabetes, and neuromuscular disorders, its specific functional impact on the pathobiology of CLTI has remained poorly understood. Until recently, it was unclear whether IMAT was merely a passive marker of advanced disease or a causative driver of the functional decline seen in these patients.
Key Content
Evidence of Adipogenic Transformation in Human PAD
Recent high-throughput molecular characterization of gastrocnemius muscle from patients across the PAD spectrum has revealed a dramatic shift in the tissue landscape as disease progresses toward CLTI. Transcriptomic and proteomic analyses indicate that while mild PAD (IC) muscle maintains a relatively normal metabolic signature, CLTI muscle exhibits a robust upregulation of genes associated with adipogenesis and lipid metabolism. Specifically, key markers such as FABP4, PLIN1, and PPARG are significantly elevated in CLTI specimens compared to non-PAD controls.
Lipidomic profiling further confirms these findings, showing an enrichment of triacylglycerols and long-chain fatty acids within the muscle parenchyma of CLTI patients. This ‘adipogenic signature’ is not merely localized to the macroscopic fat depots but is deeply integrated into the interstitial spaces between muscle fibers, suggesting a systemic reprograming of the muscle-resident progenitor cells in response to chronic ischemia.
The Role of Fibroadipogenic Progenitors (FAPs)
Single-cell and single-nucleus RNA sequencing (scRNA-seq/snRNA-seq) have identified a specific population of mesenchymal stromal cells, known as fibroadipogenic progenitors (FAPs), as the primary source of both fibrosis and IMAT in ischemic muscle. In healthy muscle, FAPs play a supportive role in muscle regeneration; however, in the setting of chronic injury and poor blood flow, these cells undergo a pathological transition. In CLTI, the FAP population expands and skews toward an adipogenic lineage rather than contributing to muscle repair.
Mechanistic Insights from Murine Models
To establish a causal link between IMAT and limb function, researchers utilized a murine model of hindlimb ischemia combined with sophisticated genetic tools. By manipulating Pparγ (peroxisome proliferator-activated receptor gamma)—the master transcriptional regulator of adipogenesis—specifically within the FAP population, investigators were able to modulate the degree of IMAT formation without affecting the initial ischemic insult.
Impact of Increasing IMAT: In mice where Pparγ was overexpressed in FAPs, there was an accelerated accumulation of IMAT following the induction of hindlimb ischemia. This increase in IMAT was directly associated with a significant reduction in muscle grip strength and a decrease in work output during treadmill exhaustion tests. Pathological analysis showed that the fat deposits physically disrupted the alignment of muscle fibers and likely impaired force transmission.
Impact of Preventing IMAT: Conversely, the genetic deletion of Pparγ in FAPs effectively blocked the formation of IMAT in the ischemic limb. These mice exhibited significantly preserved muscle architecture and superior functional performance compared to wild-type controls. Remarkably, the prevention of IMAT was sufficient to improve muscle strength even in the face of ongoing blood flow deficits, suggesting that the muscle tissue itself can be ‘rescued’ even if the vascular supply remains suboptimal.
Sex-Based Differences in IMAT Accumulation
An important finding in the study of IMAT in PAD is the influence of biological sex. In both human cohorts and animal models, females demonstrated a higher propensity for IMAT formation following ischemic injury. While the functional impact of IMAT was detrimental to both sexes, female mice exhibited a greater total volume of intramuscular fat. This may provide a biological explanation for clinical observations that female PAD patients often report worse functional status and quality of life than their male counterparts with similar degrees of arterial occlusion.
Expert Commentary
The realization that IMAT is a “key determinant” of limb function represents a significant shift in how we approach the treatment of PAD. For decades, the therapeutic focus has been almost exclusively on the macrovascular side—reopening blocked arteries via bypass surgery or endovascular intervention. However, many patients fail to recover their previous walking capacity even after successful revascularization. This study suggests that the residual ‘myopathic’ changes, specifically IMAT, may act as a permanent or semi-permanent brake on functional recovery.
From a clinical standpoint, these findings suggest that we should begin viewing IMAT as a therapeutic target in its own right. Potential strategies could include pharmacological inhibition of adipogenesis in FAPs or exercise-based interventions designed to modulate the FAP niche. Furthermore, IMAT could serve as a valuable biomarker for risk stratification; patients with high IMAT burdens at the time of diagnosis might require more aggressive physical therapy or different surgical considerations.
One limitation of current research is the need for standardized non-invasive imaging techniques (such as specialized MRI sequences) to quantify IMAT in routine clinical practice. Currently, most data rely on invasive biopsies or research-grade imaging that is not widely available. Translating these findings into the clinic will require validated imaging endpoints to monitor treatment response.
Conclusion
Intramuscular adipose tissue is no longer viewed as a benign bystander in the progression of peripheral artery disease. It is a functionally active tissue that actively impairs muscle contractility and contributes to the disability associated with CLTI. The demonstration that modulating IMAT through the Pparγ pathway can restore limb function in preclinical models provides a robust rationale for developing targeted therapies aimed at the skeletal muscle microenvironment. Future research must now focus on identifying safe, clinically applicable methods to limit IMAT formation and investigating whether existing metabolic drugs could be repurposed to improve the lives of patients suffering from the debilitating effects of PAD.
References
- Palzkill VR, Moparthy D, Yang Q, Choi J, Liu X, Kim K, Appu AB, Pass CG, Berceli SA, Sigmund CD, Scali ST, Kopinke D, Ryan TE. Intramuscular Adipose Tissue Accumulation is a Key Determinant of Limb Function in Peripheral Artery Disease. Circulation. 2026-03-10. PMID: 41804775.
- Ryan TE, et al. Mitochondrial dysfunction and muscle atrophy in peripheral artery disease. Exercise and Sport Sciences Reviews. 2019.
- Uezumi A, et al. Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. Gene Therapy. 2011.