RNA Methylation Regulates Muscle Atrophy After Nerve Damage

Peripheral nerve injuries (PNIs) can have a devastating effect on the communication between brain and muscle, triggering a cascade of detrimental consequences. One of the main consequences is muscle atrophy, which is the process of muscle mass depletion and functional decline. This atrophy not only compromises function but also poses a significant clinical challenge, with limited therapeutic options currently available.

Previous studies have shown that the imbalance between protein synthesis and degradation, particularly through pathways like the ubiquitin-proteasome system, is crucial in the development of atrophy. Additionally, various RNA changes, such as non-coding non-coding RNA expression and alternative splicing, have been shown to play a role in this process.

Emerging research has highlighted a new regulator of muscle health: m6A methylation. This reversible RNA modification, which controls gene expression, could play a significant role in combating muscle loss caused by PNIs.

In a study published in the Journal of Translational Medicine, researchers explored the changes, functions, and molecular mechanisms of m6A RNA methylation during muscle atrophy caused by denervation (nerve loss). The findings of this study suggest that m6A methylation could hold significant potential in preventing muscle loss caused by nerve damage.

The research team conducted an in-depth analysis of the muscle-wasting process triggered by PNI. A pivotal element of their investigation was assessing the levels of m6A methylation in the affected muscles. To accomplish this, they utilized the highly sensitive and specific EpiQuik m6A RNA Methylation Quantification Kit. This kit enabled them to quantify the downregulation of m6A methylation that was observed in the denervated muscles accurately. The precise measurement provided a solid foundation for further investigation into the contributing role of m6A in muscle atrophy.

To elucidate the functional role of m6A, the team conducted targeted experiments manipulating METTL3, the methyltransferase responsible for m6A deposition. The results showed that silencing METTL3 exacerbated muscle atrophy, confirming its crucial role in maintaining muscle health after PNIs. Conversely, overexpression of METTL3 significantly mitigated muscle loss, solidifying the causal relationship between m6A levels and muscle mass.

The study also revealed an intriguing neuro-muscular cross-talk facilitated by m6A methylation. In instances of nerve inactivity or denervation, there was a decrease in the release of BDNF (brain-derived neurotrophic factor), a potent initiator of m6A methylation in muscle cells. This pronounced downregulation exposed a novel mechanism contributing to the observed muscle wasting.

The findings from this study unveil potential strategies for innovative treatments to address muscle atrophy. By targeting METTL3 through pharmacological or gene therapy interventions, there is the potential to directly restore m6A levels, effectively preventing muscle loss in the aftermath of PNIs. Additionally, the modulation of BDNF signaling, achieved through restoring neuronal activity or directly stimulating BDNF production, presents an indirect means to enhance m6A methylation, providing neuroprotective benefits and concurrently improving overall muscle health.

Overall, this study reveals a promising target for addressing muscle atrophy following nerve damage through the potential involvement of m6A. While the detailed mechanisms of m6A in this context demand further investigation, the results hint at its therapeutic prospects. Further research is necessary to formulate effective treatments and enhance our understanding of m6A's role in this intricate process.

Reference:

Sun J et. al. (November 2023). Altered m6A RNA methylation governs denervation-induced muscle atrophy by regulating ubiquitin proteasome pathway. J Transl Med. 21(1):845.