Muscle stem cells as immunomodulator during regeneration.

The skeletal muscle is well known for its remarkable ability to regenerate after injuries. The regeneration is a complex and dynamic process that involves muscle stem cells (also called muscle satellite cells, MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, and other muscle-resident cell populations. The MuSCs are the myogenic cell populaiton that contribute nuclei directly to the regenerated myofibers, while the other cell types collaboratively establish a microenvironment that facilitates myogenesis of MuSCs. The myogenic process includes activation, proliferation and differentiationof MuSCs, and subsequent fusion their descendent mononuclear myocytes into multinuclear myotubes. While the contributions of FAPs and immune cells to this microenvironment have been well studied, the influence of MuSCs on other cell types remains poorly understood. This review explores recent evidence supporting the potential role of MuSCs as immunomodulators during muscle regeneration, either through cytokine production or ligand-receptor interactions.

Predictive modeling provides insight into the clinical heterogeneity associated with TARS1 loss-of-function mutations.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes that complete the first step of protein translation: ligation of amino acids to cognate tRNAs. Genes encoding ARSs have been implicated in myriad dominant and recessive phenotypes, the latter often affecting multiple tissues but with frequent involvement of the central and peripheral nervous system, liver, and lungs. Threonyl-tRNA synthetase (TARS1) encodes the enzyme that ligates threonine to tRNATHR in the cytoplasm. To date, TARS1 variants have been implicated in a recessive brittle hair phenotype. To better understand TARS1-related recessive phenotypes, we engineered three TARS1 missense mutations predicted to cause a loss-of-function effect and studied these variants in yeast and worm models. This revealed two loss-of-function mutations, including one hypomorphic allele (R433H). We next used R433H to study the effects of partial loss of TARS1 function in a compound heterozygous mouse model (R433H/null). This model presents with phenotypes reminiscent of patients with TARS1 variants and with distinct lung and skin defects. This study expands the potential clinical heterogeneity of TARS1-related recessive disease, which should guide future clinical and genetic evaluations of patient populations.

A model organism pipeline provides insight into the clinical heterogeneity of TARS1 loss-of-function variants.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes that complete the first step of protein translation: ligation of amino acids to cognate tRNAs. Genes encoding ARSs have been implicated in myriad dominant and recessive phenotypes, the latter often affecting multiple tissues but with frequent involvement of the central and peripheral nervous systems, liver, and lungs. Threonyl-tRNA synthetase (TARS1) encodes the enzyme that ligates threonine to tRNATHR in the cytoplasm. To date, TARS1 variants have been implicated in a recessive brittle hair phenotype. To better understand TARS1-related recessive phenotypes, we engineered three TARS1 missense variants at conserved residues and studied these variants in Saccharomyces cerevisiae and Caenorhabditis elegans models. This revealed two loss-of-function variants, including one hypomorphic allele (R433H). We next used R433H to study the effects of partial loss of TARS1 function in a compound heterozygous mouse model (R432H/null). This model presents with phenotypes reminiscent of patients with TARS1 variants and with distinct lung and skin defects. This study expands the potential clinical heterogeneity of TARS1-related recessive disease, which should guide future clinical and genetic evaluations of patient populations.