Highlights d A key residue variation of fast skeletal myosin allows selective targeting d A rationally designed inhibitor (MPH-220) specifically blocks skeletal muscle d The inhibitor-bound myosin atomic structure reveals mechanism of selectivity d MPH-220 improves gait disorders in spastic animal model after brain injury Authors Ma ´te ´Gyimesi, A ´da ´m I. Horva ´th,

The global prevalence of insulin resistance (IR) is increasing continuously, influencing metabolic parameters and fertility as well. The metabolic changes due to IR can alter the molecular composition of plasma and other body fluids. Follicular fluid (FF) is derived mainly from plasma, and it is a critical microenvironment for the developing oocytes. It contains various metabolites and amino acids, and the quality of the oocytes is linked at least partially to amino acid metabolism. Our goal was to determine quantitatively the amino acid (AA) profile of FF in IVF patients and to compare IR and non-insulin resistance (NIR) groups to investigate the AA changes in their FF. By UHPLC-based method we quantified the main 20 amino acids from human FF samples in the IR and NIR groups. Several amino acids (aspartate, glycine, glutamate, and cysteine) differed significantly (p<0.05 or less) between the two groups. The most significant alterations between the IR and NIR groups were related to the glutathione metabolic pathway involving glycine, serine, and threonine. Since insulin resistance alters the amino acid composition of the FF, the oocytes may undergo metabolism-induced changes resulting in poor oocyte quality and less fertility in the insulin resistance groups.

I Na,late could not be converted to an ''increasing'' morphology by application of isoproterenol, calmodulin, AP-like ramp voltage command or command APs recorded from guinea pig cells. Conventional voltage clamp experiments revealed that the ''increasing'' I Na,late profile in guinea pig is determined by the slow decay of I Na,late in this species. I Na,late was increased by isoproterenol but not by calmodulin in canine myocytes. When APs were recorded from multicellular ventricular preparations with sharp microelectrode, tetrodotoxin decreased AP duration in a reverse rate-dependent manner, which effect was the largest in human, while smaller in canine and the smallest in guinea pig preparations. The shape of I Na,late under the AP is likely determined by the different inactivation kinetics of the sodium channels that generate I Na,late . Variances between different species in the actual sodium channel subtypes that contribute to I Na,late might underlie the differences observed in the macroscopic current. Canine myocytes seems to be the best model of human ventricular cells regarding I Na,late .

Post-stroke muscle spasticity affects 37% of stroke survivors and disables self-supporting life management. There is a high unmet medical need for an efficient antispastic drug because current muscle relaxants are often of limited efficacy and cause severe neurological and cardiovascular side effects due to targeting the central or peripheral nervous system. We developed a new-generation anti-spastic oral drug, MPH-220, which efficiently relaxes spastic skeletal muscles and lacks cardiovascular and neurological adverse effects because it selectively targets skeletal myosin, the contractile protein of muscles. MPH-220 is an efficient skeletal muscle specific actomyosin relaxant demonstrated on human muscle samples. Orally administered MPH-220 reduces muscle force of living rats without cardiovascular side effects. Brain-damage induced spastic animals showed drastic improvement in gait disorders upon oral MPH-220 treatment resulting in significantly straightened body posture, reduced number of spontaneous falling and cramping, and more ordered limb positions. Due to selective accumulation of MPH-220 in skeletal muscle tissues, antispastic effect was maintained for more than 10 hours. Due to its mechanism of action MPH-220 does not cause complete loss of muscle tone even at high doses. Furthermore, MPH-220 has excellent ADMET properties for oral administration: it is highly absorptive, non-mutagenic and has no effects on hERG channels, kinases, nuclear hormone receptors and GPCRs. Considering these results, MPH-220 is a promising anti-spastic oral drug candidate, which provides potential nervous system-independent therapies for spasticity and muscle stiffness without cardiovascular and neuronal side effects. Phase I clinical trials are scheduled for the beginning of 2021. Funded by the Hungarian National Research, Development and Innovation Office (NVKP 16-1-2016-0051 and PIACI-KFI-2019-00488).

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