Skeletal Muscle Tissue Damage Leads to a Conserved Stress Response and Stem Cell-Specific Adaptive Transitions

Abstract

Every cell in a multicellular organism is dynamically interacting with its microenvironment, which determine its properties and gene-expression profile. Tissue damage, such as injury or experimental cell dissociation, leads to dramatic modifications of the microenvironment, yet the cell-type specific transcriptional responses to the stress-induced stimuli remain ill-defined. In order to identify the early events linked with tissue damage, we generated single-nucleus atlases from intact, dissociated or injured muscle and liver, and identified a common early stress response and cell-type specific transcriptional modifications. This prevalent stress response was also detected in other organs at varying levels across cell types and tissues in published datasets, demonstrating high conservation but also indicating a significant degree of data distortion in single-cell reference atlases. Skeletal muscle stem cells are mitotically quiescent during adult homeostasis and get activated in response to acute muscle damage. To further investigate the muscle stem cell-specific response to activation, we performed time course analysis, revealing that the conserved stress response is distinct and precedes the initiation of the myogenic program. Our study therefore defines the initial events governing stem cell activation in response to perturbations in tissue integrity in vivo, and identifies a broadly conserved stress response that acts in parallel to cell-specific adaptive alterations.