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Musculoskeletal injuries represent a challenging medical problem. Although the skeletal muscle is able to regenerate and recover after injury, the process engaged with conservative therapy can be inefficient, leading to a high re-injury rate. In addition, the formation of scar tissue implies an alteration of mechanical properties in muscle. There is still a need for new treatments of the injured muscle. NeuroHeal may be one option. Published studies demonstrated that it reduces muscle atrophy due to denervation and disuse. The main objective of the present work was to assess the potential of NeuroHeal to improve muscle regeneration after traumatic injury. Secondary objectives included characterizing the effect of NeuroHeal treatment on satellite cell biology. We used a rat model of sport-induced injury in the gastrocnemius and analyzed the effects of NeuroHeal on functional recovery by means of electrophysiology and tetanic force analysis. These studies were accompanied by immunohistochemistry of the injured muscle to analyze fibrosis, satellite cell state, and fiber type. In addition, we used an in vitro model to determine the effect of NeuroHeal on myoblast biology and partially decipher its mechanism of action. The results showed that NeuroHeal treatment advanced muscle fiber recovery after injury in a preclinical model of muscle injury, and significantly reduced the formation of scar tissue. In vitro, we observed that NeuroHeal accelerated the formation of myotubes. The results pave the way for novel therapeutic avenues for muscle/tendinous disorders.

Muscle wasting is an unmet medical need which leads to a reduction of myofiber diameter and a negative impact on the functional performance of daily activities. We previously found that a new neuroprotective drug called NeuroHeal reduced muscle atrophy produced by transient denervation. Aiming to decipher whether NeuroHeal has a direct role in muscle biology, we used herein different models of muscle atrophy: one caused by chronic denervation, another caused by hindlimb immobilization, and lastly, an in vitro model of myotube atrophy with Tumor Necrosis Factor-α (TNFα). In all these models, we observed that NeuroHeal reduced muscle atrophy and that SIRT1 activation seems to be required for that. The treatment downregulated some critical markers of protein degradation: Muscle Ring Finger 1 (MuRF1), K48 poly-Ub chains, and p62/SQSTM1. Moreover, it seems to restore the autophagy flux associated with denervation. Hence, we envisage a prospective use of NeuroHeal at clinics for different myopathies., Competing Interests: The authors declare no conflict of interest. NeuroHeal use for muscle disorders is under patent review.

Rationale : Protective mechanisms allow healthy neurons to cope with diverse stresses. Excessive damage as well as aging can lead to defective functioning of these mechanisms. We recently designed NeuroHeal using artificial intelligence with the goal of bolstering endogenous neuroprotective mechanisms. Understanding the key nodes involved in neuroprotection will allow us to identify even more effective strategies for treatment of neurodegenerative diseases. Methods : We used a model of peripheral nerve axotomy in rat pups, that induces retrograde apoptotic death of motoneurons. Nourishing mothers received treatment with vehicle, NeuroHeal or NeuroHeal plus nicotinamide, an inhibitor of sirtuins, and analysis of the pups were performed by immunohistochemistry, electron microscopy, and immunoblotting. In vitro , the post-translational status of proteins of interest was detailed using organotypic spinal cord cultures and genetic modifications in cell lines to unravel the neuroprotective mechanisms involved. Results : We found that the concomitant activation of the NAD + -dependent deacetylase SIRT1 and the PI3K/AKT signaling pathway converge to increase the presence of deacetylated and phosphorylated FOXO3a, a transcription factor, in the nucleus. This favors the activation of autophagy, a pro-survival process, and prevents pro-apoptotic PARP1/2 cleavage. Major conclusion : NeuroHeal is a neuroprotective agent for neonatal motoneurons that fine-tunes autophagy on by converging SIRT1/AKT/FOXO3a axis. NeuroHeal is a combo of repurposed drugs that allow its readiness for prospective pediatric use., Competing Interests: Competing Interests: The authors have declared that no competing interest exists. NeuroHeal is currently under patent protection., (© The author(s).)