Skeletal myogenesis is a highly coordinated process that includes satellite cell activation, cell-cycle exit, and fusion of mononucleated myoblasts resulting in multinucleated myofibers. Many signaling pathways regulate the expression of myogenic genes and eventually the myogenesis process. Dysregulation of this process may exacerbate pathological conditions such as muscular dystrophy, cachexia, and sarcopenia. This has important clinical implications, since sarcopenia is an important conditioning factor in situations such as aging and many muscle diseases, especially on a genetic basis, such as muscular dystrophies, but also some neurodegenerative diseases with muscle implication, such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy (SMA). Researchers report that a protein known to be important to protein synthesis also influences muscle regeneration and regrowth in an unexpected manner. The discovery, could one day lead to new methods for treating disorders that result in muscle weakness and loss of muscle mass.
Scientists have long studied leucine tRNA-synthetase, or LRS, for its role in protein synthesis. This enzyme loads the aminoacid leucine to address it for a new protein synthesis during RNA translation. But, looks like that it has additional roles inside the cells. Giving a little example, glutamine tRNA synthetase (QRS), beside loading glutamine for the same process, it is a cellular inhibitor of ASK-1, a protein kinase that enhances programmed cell death (apoptosis). Dr Chen and her colleagues used mammalian cell cultures and mice in the new study. They compared the speed of muscle repair in mice with normal and lower-than-normal LRS levels. They discovered that mice with lower levels of LRS in their tissues recovered from muscle injury much more quickly than their counterparts with normal LRS levels. While it is not possible to lower LRS in human subjects, the researchers sought another method to block its effects. The team further unraveled the exact molecular mechanism by which LRS influences muscle regeneration, using a pharmacological and molecular approach.
They hypothesized that a nontoxic inhibitor that their collaborators in South Korea previously developed, would block the effect of LRS on muscle cells without interfering with its role in protein synthesis. LRS is regulated by a small protein called Rag, which in turn influences the mTORC pathway, a complex of proteins that drives cellular protein synthesis. Firstly, the team demonstrated that the LRS-Rag-mTORC1 pathway paradoxically blocks the formation of new muscle fibers. On the contrary, skeletal muscle–specific knock out of Raptor lead to muscle dystrophy in mice, suggesting a positive role of mTORC1 in muscle maintenance. They showed that this inhibitor works both in mammalian cells and in mice. BC-LI-0186, has been developed to directly interact with LRS, disrupt binding of LRS to Rag, and inhibit leucine-dependent activation of mTORC1 in cells with high specificity, without affecting the enzymatic activity of LRS. Muscle repair occurred more rapidly – and the regenerated muscles were stronger – when the inhibitor was present.
Leader professor Jie Chen of Cell and Developmental biology at the University of Illinois, explained some parts of the research: “In the last 5-10 years, scientists have begun to realize that LRS and other proteins like it have functions independent of protein synthesis. Previously, my lab and other labs discovered that one of such functions of LRS is that it can regulate cell growth. Our new study is the first report of its function in muscle regeneration. A 70% reduction of LRS proteins in the cell does not affect protein synthesis. But lower levels do positively influence muscle regeneration. We saw that, seven days after injury, the repaired muscle cells are bigger when LRS is lower. Clearly, this enzyme is what is already known as a “moonlighting” protein. We now understand that ‘protein moonlighting’, where one protein does many different things in the cell, is the norm”. The whole research is already published in the Journal of Clinical Investigation.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Son K et al. Chen J. J Clin Invest. 2019 Apr 15; 130:2088.
Yoon S et al. Bioorg Med Chem. 2019 Mar 15; 27(6):1099.
Zamacona R et al. Curr Drug Discov Technol. 2018 Aug 7.
Yoon S et al. Bioorg Med Chem. 2018 Aug 7; 26(14):4073.
Dott. Gianfrancesco Cormaci
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