microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism

Area of Science:

• Molecular Biology
• Skeletal Muscle Physiology
• Metabolic Regulation

Background:

• MicroRNA-1 (miR-1) is highly abundant in adult skeletal muscle.
• The precise function of miR-1 in adult skeletal muscle metabolism remains incompletely understood.

Purpose of the Study:

• To elucidate the functional role of miR-1 in adult skeletal muscle.
• To identify miR-1 target genes and understand its regulatory mechanisms in muscle metabolism.

Main Methods:

• Generation of an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse model.
• Integration of RNA-sequencing (RNA-seq) and Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) data.
• Comprehensive bioenergetic, metabolic, proteomic, and metabolomic phenotyping.

Main Results:

• Loss of miR-1 induced cancer-like metabolic reprogramming, increasing pyruvate kinase muscle isozyme M2 (PKM2) and promoting glycolysis.
• miR-1 deficiency resulted in metabolic inflexibility due to pyruvate oxidation resistance.
• Genetic loss of miR-1 impaired endurance exercise performance in mice and C. elegans.

Conclusions:

• miR-1 is a critical regulator of adult skeletal muscle metabolism, controlling glycolysis and pyruvate oxidation.
• Down-regulation of miR-1, observed during hypertrophy, supports muscle growth through metabolic reprogramming.
• Identified a novel post-translational mechanism for skeletal muscle metabolism regulation mediated by miR-1.