IGF2 deficiency induces sarcopenia and muscle functional decline

Background and aims: Insulin-like growth factor 2 (IGF2) is closely associated with the occurrence and development of primary and secondary muscle atrophy. This study investigates the role of IGF2 deficiency in inducing muscle atrophy using muscle-specific Igf2 knockout mice, aiming to provide theoretical basis and new concepts for growth hormone supplementation therapy in muscle atrophy. Methods: We analyzed Igf2 expression using the Tabula Muris single-cell database and generated muscle-specific Igf2 knockout mice using the Cre/LoxP system with Mck-cre transgenic mice. We characterized the phenotype and assessed muscle size and mass through external observation, dissection, H&E staining, and microCT scanning. Muscle function was evaluated using the Md3000 grip strength meter, treadmill tests for endurance and electromyography (EMG) for contraction force. Transcriptome sequencing was performed on muscle tissues to analyze the impact of Igf2 deletion on gene expression and pathways. Results: The Tabula Muris database confirmed high Igf2 expression in limb muscles, and we successfully developed muscle-specific Igf2 knockout (Igf2 cKO) mice. Analyses using MicroCT and H&E staining showed reduced muscle size, weight, and density in the gastrocnemius of Igf2 cKO mice versus controls. Grip strength tests using the Md3000 animal grip strength meter and treadmill tests assessing running endurance both indicated reduced physical performance in the Igf2 cKO group, with weakened grip strength and decreased running endurance distance and time. Electromyography (EMG) measurements disclosed a decrease in gastrocnemius muscle contraction force in the Igf2 cKO group. Transcriptome sequencing highlighted significant functional changes in muscle-related processes, RNA polymerase II transcription, and the PI3K pathway in the Igf2 cKO mice. Conclusions: Igf2 is highly expressed in skeletal muscle tissue. Muscle-specific Igf2 knockout mice exhibited reduced muscle size, weight, and density, weakened grip strength, decreased gastrocnemius muscle contraction force, and reduced running endurance distance and time. These findings suggest that IGF2 supplementation may be a potentially effective strategy for treating muscle atrophy. Overall design: Global transcriptome profiling was performed by RNA-Seq using muscle tissues of Control Igf2f/f and Igf2 cKO mice (n=3). RNA was extracted, sequenced, and analyzed by a custom service provided by Novogene using an Illumina NovaSeq 6000. Bioinformatics analysis was performed using the OmicStudio tools at https://www.omicstudio.cn/tool. The cut-off for differential expression threshold was based on | (log2FC) |> 1 and p-value < 0.05.