Hmgcr, or 3-hydroxy-3-methylglutaryl-CoA reductase, is a key enzyme in the cholesterol synthesis pathway, catalyzing a crucial step in this process [2]. The mevalonate pathway, in which Hmgcr is involved, is essential for various cellular functions such as the synthesis of cholesterol and other isoprenoids, which are important for cell membrane integrity, signal transduction, and protein prenylation [1].

Knockdown of Hmgcr in mouse skeletal myoblasts and Drosophila revealed its significance in skeletal muscle development. Hmgcr deficiency led to decreased proliferation, increased apoptosis, and impaired myotube fusion in mouse myoblasts, with differential expression in mitochondrial function-related genes and corresponding changes in oxygen consumption rates. In Drosophila, both ubiquitous and muscle-specific knockdown of hmgcr led to lethality. Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, while pathogenic variants did not, suggesting shared disease mechanisms in HMGCR-related muscle diseases [2].

In conclusion, Hmgcr is vital for cholesterol synthesis and plays a significant role in skeletal muscle development. Studies using gene knockdown models in mice and Drosophila have provided insights into the mechanisms underlying HMGCR-related muscle diseases, such as limb-girdle muscular dystrophy, statin-associated myopathy, and autoimmune anti-HMGCR myopathy [2].

References:

1. Pokhrel, Ram Hari, Acharya, Suman, Ahn, Jae-Hee, Ko, Hyun-Jeong, Chang, Jae-Hoon. 2021. AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway. In Molecular cancer, 20, 133. doi:10.1186/s12943-021-01420-9. https://pubmed.ncbi.nlm.nih.gov/34649584/

2. Gunasekaran, Mekala, Littel, Hannah R, Wells, Natalya M, Pacak, Christina A, Kang, Peter B. 2024. Effects of HMGCR deficiency on skeletal muscle development. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.05.06.591934. https://pubmed.ncbi.nlm.nih.gov/38903061/