Integrative Multi-Omics Analysis Identifies Tissue, Cellular and Splicing Programs Associated with Exercise-Mediated...

Area of Science:

• Genetics and Genomics
• Metabolic Diseases
• Exercise Physiology

Background:

• Physical inactivity is a major contributor to type 2 diabetes (T2D).
• The molecular mechanisms connecting exercise, metabolic health, and T2D are not fully understood.
• Genetic factors play a role in both physical activity response and T2D susceptibility.

Purpose of the Study:

• To elucidate the molecular links between vigorous physical activity, T2D risk, and metabolic improvement.
• To integrate multi-omics data and experimental models to identify shared genetic and regulatory pathways.
• To investigate the role of specific genes, such as Mau2, in exercise response and T2D.

Main Methods:

• Meta-analysis of genome-wide association studies (GWAS) for physical activity and T2D (n ≈ 1.95 million).
• Integration of eQTL/sQTL data with single-cell and spatial transcriptomics.
• Computational analyses including enrichment, colocalization, and network analyses.
• Experimental validation in a mouse model of diet-induced diabetes with an exercise intervention.

Main Results:

• Exercise and T2D-associated genetic variants are jointly enriched in skeletal muscle and adipose tissue.
• Fibro-adipogenic progenitors and endothelial cells were prioritized in single-cell analyses.
• A gene module related to extracellular matrix and collagen in fibro-adipogenic progenitors was associated with both exercise and T2D.
• The gene Mau2 showed tissue-specific splicing signals and was identified as a shared candidate.
• Exercise improved glucose homeostasis and muscle structure in diabetic mice, reducing Mau2 intron retention.

Conclusions:

• A multiscale framework connects exercise-responsive gene regulation to T2D-related tissue remodeling and splicing plasticity.
• Specific cell types and molecular pathways, including Mau2 splicing, are critical mediators of exercise benefits in T2D.
• Genetic insights from large-scale studies combined with experimental models provide a comprehensive understanding of exercise and metabolic health.