Computational Identification of Dithymoquinone as a Potential Inhibitor of Myostatin and Regulator of Muscle Mass

Syed Sayeed Ahmad,Sibhghatulla Shaikh,Eun Ju Lee,Khurshid Ahmad,Inho Choi

doi:10.3390/molecules26175407

Abstract

The skeletal muscle (SM) is the largest organ in the body and has tremendous regenerative power due to its myogenic stem cell population. Myostatin (MSTN), a protein produced by SM, is released into the bloodstream and is responsible for age-related reduced muscle fiber development. The objective of this study was to identify the natural compounds that inhibit MSTN with therapeutic potential for the management of age-related disorders, specifically muscle atrophy and sarcopenia. Sequential screening of 2000 natural compounds was performed, and dithymoquinone (DTQ) was found to inhibit MSTN with a binding free energy of −7.40 kcal/mol. Furthermore, the docking results showed that DTQ reduced the binding interaction between MSTN and its receptor, activin receptor type-2B (ActR2B). The global energy of MSTN-ActR2B was found to be reduced from −47.75 to −40.45 by DTQ. The stability of the DTQ–MSTN complex was subjected to a molecular dynamics analysis for up to 100 ns to check the stability of the complex using RMSD, RMSF, Rg, SASA, and H-bond number. The complex was found to be stable after 10 ns to the end of the simulation. These results suggest that DTQ blocks MSTN signaling through ActR2B and that it has potential use as a muscle growth-promoting agent during the aging process.

Highlights

Human skeletal muscle (SM) is a highly plastic tissue that accounts for up to 40% of total body weight and 50–75% of body protein [1]
The maintenance of SM mass depends on the balance between protein synthesis and degradation, which are highly sensitive to hormonal balance, nutritional status, exercise, injury, and disease [4]
Compounds with a binding free energy of better than −6.0 kcal/mol (20 compounds shown in Table S1) were considered for further analysis

Summary

Introduction

Human skeletal muscle (SM) is a highly plastic tissue that accounts for up to 40% of total body weight and 50–75% of body protein [1]. SM is the largest body organ and is mainly responsible for movement, temperature control, and maintaining glucose levels because muscle contraction utilizes glucose as a fuel source [2]. SM has considerable regenerative potential in response to damage or disease due to its myogenic stem cell population [3]. The maintenance of SM mass depends on the balance between protein synthesis and degradation, which are highly sensitive to hormonal balance, nutritional status, exercise, injury, and disease [4]. Aging is a difficult issue to address and has become a priority due to rapid increases in elderly populations and age-related diseases [10]

Objectives

Methods

Results

Conclusion