Background: Myotonic dystrophy type 1 (DM1) extends far beyond skeletal muscle dysfunction. Emerging evidence suggests that chronic inflammation plays a pivotal role in disease progression; however, the specific inflammatory mediators involved and their spatial organization within affected tissues remain poorly understood. To date, no study has integrated systemic inflammatory profiling with high-resolution spatial mapping of the muscle microenvironment in DM1.
Objectives: We conducted the first integrated analysis combining comprehensive plasma inflammatory profiling with spatial transcriptomics of muscle biopsies to define the inflammatory landscape of DM1.
Methods: Plasma samples from 19 DM1 patients and 17 healthy controls underwent inflammatory profiling using the Olink 92-protein targeted panel. Significantly altered proteins were further analyzed using STRING network analysis to identify functional interactions. High-resolution spatial transcriptomics (Xenium, 5K gene panel) is being performed on tibialis anterior muscle biopsies to determine how inflammatory gene signatures are spatially organized within the muscle microenvironment.
Results: Eight inflammatory proteins showed significant alterations (P≤0.05), with CD8A, a marker of cytotoxic T cell activation, surviving FDR correction, highlighting adaptive immune engagement. The dysregulated network encompasses chemokine signaling (CX3CL1, IL-8), T cell and natural killer cell function (CD8A, CD244), cytokine regulation (TSLP, TWEAK), cellular stress responses (4E-BP1), and Notch signaling (DNER). STRING analysis further revealed unexpected interconnections, suggesting coordinated inflammatory responses. Ongoing spatial transcriptomics will reveal how these systemically elevated markers are spatially distributed within muscle tissue, potentially uncovering distinct inflammatory microdomains, cell-type-specific expression patterns, and their relationship to muscle pathology.
Conclusions: This pioneering multi-scale approach reveals that DM1 is characterized by sophisticated inflammatory signatures spanning systemic circulation and tissue architecture. Integrating plasma inflammatory profiles with spatial tissue mapping will provide critical insights into localized immune mechanisms in DM1 and may identify specific inflammatory niches as therapeutic targets, enabling precision immunomodulatory strategies to slow disease progression and improve patient outcomes.