MYL3, also known as myosin light chain 3, is a gene encoding a protein that is part of the sarcomere, playing a crucial role in muscle contraction. The sarcomere is a fundamental unit in muscle tissue, and MYL3's function is essential for normal muscle function. Genetic models, such as KO or CKO mouse models, are valuable tools for studying MYL3's function.

In chondrocytes, MYL3 protein levels decline in senescent cells from model mice and osteoarthritis (OA) patients. Conditional deletion of Myl3 in chondrocytes promotes OA progression in male mice, while intra-articular injection of adeno-associated virus overexpressing MYL3 delays it. MYL3 deficiency enhances clathrin-mediated endocytosis by promoting the interaction between myosin VI and clathrin, leading to Notch activation in chondrocytes [1].

In the context of hypertrophic cardiomyopathy (HCM), MYL3 is among the core sarcomeric genes. Mutations in MYL3 are associated with HCM, and genetic testing for HCM often includes analysis of MYL3. In a study of Norwegian HCM probands, MYL3 was one of the genes analyzed, with mutations found in a subset of patients [2]. Pediatric HCM patients have more MYL3 variants compared to adults, and in a meta-analysis, the penetrance of MYL3 in non-proband relatives carrying pathogenic/likely pathogenic variants was around 32% [3,4]. Homozygous loss-of-function variants in MYL3 can cause autosomal recessive cardiomyopathy and sudden cardiac death, as shown by exome sequencing in consanguineous families and functional assessment in zebrafish [5].

In conclusion, MYL3 is essential for normal muscle function, being a key component of the sarcomere. Model-based research, including KO/CKO mouse models and other functional studies, has revealed its role in processes such as chondrocyte senescence and OA development, as well as its association with cardiomyopathies like HCM. Understanding MYL3's function provides insights into the mechanisms of these diseases, potentially guiding future therapeutic strategies.