Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury

Area of Science:

• Biomedical Engineering
• Regenerative Medicine
• Neuroscience

Background:

• Peripheral Nerve Injuries (PNI) cause significant long-term disability due to muscle denervation and atrophy.
• Slow axon regeneration hinders muscle reinnervation, leading to irreversible muscle fiber damage.

Purpose of the Study:

• To investigate if reprogramming skeletal muscle to an embryonic-like state can preserve reinnervation capacity after PNI.
• To evaluate the therapeutic potential of NANOG expression in muscle for PNI recovery.

Main Methods:

• Developed a mouse model for inducible NANOG expression in muscle via doxycycline.
• Utilized a sciatic nerve transection model to induce PNI.
• Assessed muscle development, gene expression, neuromuscular junction (NMJ) integrity, and motor function recovery.

Main Results:

• NANOG expression upregulated muscle development genes (Pax7, eMYHC) and promoted myogenesis, neurogenesis, and NMJ formation.
• NANOG-treated mice showed restored innervation with significant overlap between synaptic vesicles and NMJ acetylcholine receptors (AChRs).
• Improved motor function recovery, including enhanced toe-spread reflex, EMG responses, and isometric force production, was observed in NANOG mice compared to controls.

Conclusions:

• Skeletal muscle reprogramming via NANOG is a promising strategy to enhance reinnervation after PNI.
• This approach can improve functional outcomes and potentially reduce long-term disability associated with nerve injuries.