A Validated Transcriptomic NMJ Remodeling Score Reveals Synaptic Dysfunction Independent of Muscle Atrophy after...

Area of Science:

• Muscle physiology
• Neuroscience
• Molecular biology

Background:

• Immobilization leads to muscle weakness exceeding that explained by muscle mass loss alone.
• Neuromuscular synaptic changes are implicated in immobilization-induced muscle weakness.

Purpose of the Study:

• To quantify transcriptomic adaptations at the neuromuscular junction (NMJ) during short-term unloading.
• To compare NMJ remodeling with classical atrophy pathways.

Main Methods:

• Developed a composite transcriptomic NMJ Remodeling Score using RNA sequencing data from vastus lateralis.
• Analyzed gene expression changes in adults undergoing 10 days of lower-limb suspension and 21 days of recovery.
• Evaluated NMJ and atrophy scores across >20,000 genes, with replication in a bed rest cohort.

Main Results:

• Limb unloading induced a significant increase in the NMJ score, partially normalizing with recovery.
• The atrophy score increased more sharply and fully reversed during recovery, showing weak correlation with the NMJ score.
• NMJ gene expression revealed upregulation of acetylcholine receptor subunits and downregulation of MuSK, suggesting a denervation-like pattern.

Conclusions:

• Limb unloading causes measurable transcriptomic remodeling at the NMJ, independent of atrophy signaling.
• These findings provide a framework for studying neural contributions to immobilization-induced muscle weakness.
• The distinct NMJ remodeling suggests targeted interventions may mitigate weakness beyond addressing muscle mass loss.