# Dissecting myogenic-endothelial-immune interactomes in human ME/CFS skeletal muscles

> **NIH NIH U54** · CORNELL UNIVERSITY · 2024 · $540,936

## Abstract

PROJECT 1: ABSTRACT/SUMMARY
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous debilitating disorder
characterized by severe disabling fatigue, especially post-exertion, in the absence of alternative diagnosis. The
etiology of ME/CFS remains unknown and underexplored and is likely multifaceted. Given the prevalence of
muscle fatigue symptoms, the pathophysiology of skeletal muscle has received attention in ME/CFS studies.
Skeletal muscles of ME/CFS individuals do not exhibit overt changes in muscle fiber architecture, quality, or
type, though studies have identified altered muscle metabolism, peripheral vascular dysfunction, and local and
systemic inflammation as potential mediators of CE/MFS. This project will address the premise that skeletal
muscle dysfunction in ME/CFS arises from a multifaceted and heterogeneous dysregulation of myogenic,
vascular endothelial, and immune cell identities and interactions in skeletal muscles. Myogenic cells and resident
immune and vascular endothelial cells are in close proximity and have varied interactions through cell-cell
signaling pathways and coupled metabolic programs that are critical for muscle health and disease. Here, we
will collect a new cohort of ME/CFS and control skeletal muscle biopsies to investigate the interactions between
myogenic, endothelial, and muscle-resident immune cells using innovative single-cell technologies. First, we will
collect a new cohort of skeletal muscle biopsies and blood samples from ME/CFS patients (n = 40) and healthy
controls (n = 20), along with accompanying survey and physiological data (grip strength and orthostatic vascular
function). Building on our prior track record of generating a multi-donor scRNAseq atlas in human skeletal
muscle, we will analyze these new biopsies by single-nucleus paired RNA/ATAC-sequencing (snRNA/ATACseq)
and a novel method of spatial total RNA-sequencing (STRS). snRNA/ATACseq will reveal changes in cellular
identities and compositions, as well as alterations in metabolic and transcriptional programs through various
bioinformatic analyses. STRS will reveal changes in the spatial mapping of muscle cell types and their noncoding
(e.g., regulatory miRNA and lncRNA) RNA profiles. Together these data will be integrated to identify changes in
cell-cell communication (ligand-receptor) pathways involving myogenic, endothelial, and immune cells and their
spatial organization between control and ME/CFS muscles. Various metrics from these single-cell datasets will
be tested through association studies as possible biomarkers that may explain the heterogeneous manifestations
of ME/CFS in this patient cohort. Third, hypotheses related to signaling interactions driving endothelial
dysfunction in ME/CFS skeletal muscles will be evaluated using cell culture models involving skeletal muscle-
specific human endothelial cells exposed to plasma and monocytes isolated from ME/CFS or control samples.
Together, these aims may shed l...

## Key facts

- **NIH application ID:** 10827452
- **Project number:** 5U54AI178855-07
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Benjamin David Cosgrove
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $540,936
- **Award type:** 5
- **Project period:** 2017-09-30 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827452

## Citation

> US National Institutes of Health, RePORTER application 10827452, Dissecting myogenic-endothelial-immune interactomes in human ME/CFS skeletal muscles (5U54AI178855-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10827452. Licensed CC0.

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