From histology to omics: a spatial atlas of muscle fiber-type architecture in health and disease

Abstract

Skeletal muscle is among of the largest and most metabolically active organs in the human body. Through its primary function of generating force, skeletal muscles play a central role in major physiological processes, including movement, respiration, digestion and metabolic homeostasis. Myofibers are the contractile units responsible for force generation, and different fiber types determine the contractile speed, force output, and metabolic profile of different muscles. Over the past decades, advances in omics technologies have expanded our knowledge on how molecular pathways shape skeletal muscle heterogeneity. However, despite these advances, it remains poorly understood whether molecular and cellular heterogeneity is spatially organized across intact skeletal muscles.

This thesis addresses this knowledge gap by systematically mapping the spatial organization of skeletal muscle across multiple molecular layers. By integrating spatial transcriptomics, spatial metabolomics, epigenetics, and histology, it characterizes how gene expression, metabolism, fiber-type composition, and DNA methylation are distributed across whole muscles in healthy and dystrophic conditions. Together, these approaches generate a spatial atlas of muscle architecture, providing new insight into muscle heterogeneity and its implications for muscle function and disease.