Effects of HMGCR deficiency on skeletal muscle development

Abstract

AbstractPathogenic variants inHMGCRwere recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. The mechanism linking pathogenic variants inHMGCRwith skeletal muscle dysfunction is unclear. We knocked downHmgcrin mouse skeletal myoblasts, knocked downhmgcrin Drosophila, and expressed three pathogenicHMGCRvariants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) inHmgcrknockdown mouse myoblasts.Hmgcrdeficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing ofHmgcrknockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown ofhmgcrin Drosophila led to lethality. Overexpression of referenceHMGCRcDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants ofHMGCRcDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.