NeuroHeal Reduces Muscle Atrophy and Modulates Associated Autophagy

Abstract

<jats:p>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.</jats:p>

Sirtuins' control of autophagy and mitophagy in cancer

“…Under starvation, p62 requires acetylation by TIP60 to significantly enhance its ubiquitin binding and p62 clustering, and p62 is deacetylated by HDAC6. However, TIP60 activity is modulated negatively by SIRT1 but, NeuroHeal increases SIRT1 activity and hence would probably diminish TIP60 acetylation slowing down p62 clustering (Marmolejo-Martinez-Artesero et al, 2020). Somehow, these observations indicate that softening the autophagy process favors a good resolution.…”

“…Towards this path, recently, Marmolejo-Martínez-Artesero S et al have shown that NeuroHeal, a novel neuroprotective drug, has a direct effect on muscle biology. This new drug reduces neurogenic and non-neurogenic myopathy, promotes decreased proteasomal activity and improved autophagic flow activating SIRT1 to prevent muscle atrophy (Marmolejo-Martinez-Artesero et al, 2020). In fact, autophagy plays an important role in eliminating misfolded and non-functioning proteins thanks to the p62/ SQSTM1 receptor.…”

NeuroHeal Improves Muscle Regeneration after Injury

“…Although NeuroHeal was discovered to act on the nervous system, in previous studies, we observed that it also reduces muscle atrophy caused by denervation [ 12 ] and by hindlimb immobilization [ 17 ]. For that reason, we pursued to decipher whether it may act on muscle cell biology as well by using a rat model of sports-type muscle injury [ 20 ].…”

“…We have previously reported its neuroprotective effects in different neurodegenerative models [ 12 , 14 , 15 , 16 ]. In addition, we recently observed that NeuroHeal protects the muscle by reducing atrophy induced by denervation or by immobilization [ 17 ], suggesting it may have also protective effects in other types of myopathies. NeuroHeal neuroprotective and neurodegenerative effects involve SIRT1 activation, and autophagy modulation [ 14 , 15 , 18 ].…”

“…NeuroHeal neuroprotective and neurodegenerative effects involve SIRT1 activation, and autophagy modulation [ 14 , 15 , 18 ]. Moreover, we have recently described that boosting SIRT1 activity is essential in the mechanism of action of NeuroHeal to reduce muscle atrophy [ 17 ]. Herein, we aimed to elucidate whether NeuroHeal has an effect on muscle regeneration by using an in vivo model of surgically-induced lesion which mimics the most frequent skeletal muscle lesions observed in human sports clinics.…”