Network-based modelling reveals cell-type enriched patterns of non-coding RNA regulation during human skeletal muscle...

Area of Science:

• Molecular Biology
• Genomics
• Human Physiology

Background:

• Non-protein-coding RNAs (ncRNAs) play crucial roles in human development and disease.
• Studying ncRNA in human skeletal muscle is challenging due to limitations of short-read sequencing.
• Understanding ncRNA's role in muscle hypertrophy is essential for regenerative medicine and sports science.

Purpose of the Study:

• To investigate cell-type specific ncRNA responses during human skeletal muscle growth at scale.
• To identify novel ncRNAs associated with muscle hypertrophy using advanced sequencing and network modeling.
• To elucidate the functional pathways and cell types involved in ncRNA-mediated muscle growth.

Main Methods:

• Conducted five human resistance-training studies with 144 participants, identifying responders and non-responders to muscle mass accrual.
• Generated 288 transcriptome-wide profiles using a customized RNA sequencing pipeline.
• Employed network modeling to analyze interactions between ncRNAs and muscle growth pathways at the single-cell level.

Main Results:

• Identified 110 ncRNAs significantly linked to muscle growth in vivo, including known regulators like CYTOR and novel candidates.
• Discovered novel hypertrophy-linked ncRNAs: PPP1CB-DT (myofibril assembly), EEF1A1P24, and TMSB4XP8 (vascular remodeling/angiogenesis).
• Demonstrated that hypertrophy-related ncRNAs like MYREM exhibit specific myonuclear expression patterns and mediate effects via multiple cell types and pathways.

Conclusions:

• Single-cell associated ncRNAs can be identified from bulk muscle transcriptomic data.
• Hypertrophy-linked ncRNA genes are associated with muscle growth through diverse cell types and interacting pathways.
• This study provides a comprehensive resource for understanding ncRNA's role in human skeletal muscle adaptation and disease.