Mitochondrial dysfunction in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) immune-mediated necrotising myopathy

Acosta, Ignacio; Hofer, Monika; Brady, Stefen

doi:10.1016/j.nmd.2022.03.005

Cited by 4 publications

(6 citation statements)

References 11 publications

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“…Ccf‐mtDNA levels are elevated in IIMs patients with AMAs, IMNM patients, DM patients, and ASS patients, and there is no significance between IIMs patients with AMAs and IMNM patients, DM patients, or ASS patients. And mitochondrial alterations in skeletal muscle biopsies from IIMs patients with AMAs ranged from 28.6% to 52.0%, 7,8 similar to the findings reported in other subtypes of IIMs 43–45 . We guess that mitochondrial dysfunction partially contributes to the pathogenesis of AMA‐associated IIMs, although mitochondrial damage exists but not unique in AMA‐associated IIMs.…”

Section: Discussionsupporting

confidence: 80%

“…And mitochondrial alterations in skeletal muscle biopsies from IIMs patients with AMAs ranged from 28.6% to 52.0%, 7,8 similar to the findings reported in other subtypes of IIMs. [43][44][45] We guess that mitochondrial dysfunction partially contributes to the pathogenesis of AMA-associated IIMs, although mitochondrial damage exists but not unique in AMA-associated IIMs. Ccf-nDNA is primarily released into the bloodstream from various cellular processes, including NETosis, apoptosis, and necrosis.…”

Section: Discussionmentioning

confidence: 95%

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Clinicopathological and circulating cell‐free DNA profile in myositis associated with anti‐mitochondrial antibody

Wang,

Zhao,

et al. 2023

Ann Clin Transl Neurol

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ObjectiveAnti‐mitochondrial antibodies (AMAs) are associated with idiopathic inflammatory myopathies (IIMs). We aimed to summarize the clinicopathological characteristics, assess circulating cell‐free mitochondrial DNA (ccf‐mtDNA), and circulating cell‐free nuclear DNA (ccf‐nDNA) in AMA‐associated IIMs.MethodsMedical records of 37 IIMs patients with AMAs were reviewed. Circulating cell‐free mtDNA and ccf‐nDNA levels in sera from IIMs patients with AMAs (n = 21), disease controls (n = 66) and healthy controls (HCs) (n = 23) were measured and compared. Twenty‐eight immune‐mediated necrotizing myopathy (IMNM) patients, 23 dermatomyositis (DM) patients, and 15 anti‐synthetase syndrome (ASS) patients were enrolled as disease controls. Correlations between variables were analyzed.ResultsLimb weakness was observed in 75.7% and neck weakness in 56.8% of patients. Cardiac involvement occurred in 51.4% of patients. Muscle pathology revealed 81.1% of IMNM, 5.4% polymyositis, and 13.5% nonspecific myositis. Microinfarction was observed in 8.1% of patients. Serum ccf‐mtDNA levels in AMA‐associated IIMs were significantly higher than those in HCs (p < 0.001), but no significant differences between AMA‐associated IIMs and IMNM, DM, or ASS. Serum ccf‐nDNA levels in AMA‐associated IIMs were significantly higher than those in HCs (p = 0.02), and significantly lower than those in DM (p = 0.02). Serum ccf‐nDNA levels correlated negatively with MMT8 total scores (rs = −0.458, p = 0.037) and positively with mRS scores (rs = 0.486, p = 0.025). Serum ccf‐nDNA levels were significantly higher in the non‐remission group (p < 0.01).InterpretationAMA‐associated IIMs exhibit distinct clinicopathological features. Serum ccf‐nDNA may serve as a potential marker for disease severity and prognosis in AMA‐associated IIMs.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 95%

Clinicopathological and circulating cell‐free DNA profile in myositis associated with anti‐mitochondrial antibody

Wang,

Zhao,

et al. 2023

Ann Clin Transl Neurol

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“…Knockdown of hmgcr in mature myofibers in Drosophila using the Mhc-Gal4 driver results in viable flies with decreased locomotor activity and fragmented mitochondria 20 , indicating that hmgcr deficiency is consequential both during development and in mature flies, with a more severe phenotype when knocked down earlier in life. SAM is associated with mitochondrial oxidative stress 29 and mitochondrial dysfunction has been noted on muscle biopsy of a human with anti-HMGCR immune-mediated myopathy 30 . Our cDNAseq data, along with the OCR and MTT findings, demonstrate that the cellular phenotype of Hmgcr knockdown is accompanied by elevated mitochondrial respiration.…”

Section: Discussionmentioning

confidence: 99%

Effects of HMGCR deficiency on skeletal muscle development

Gunasekaran,

Littel,

Wells

et al. 2024

Preprint

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Pathogenic variants in HMGCR were 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 in HMGCR with skeletal muscle dysfunction is unclear. We knocked down Hmgcr in mouse skeletal myoblasts, knocked down hmgcr in Drosophila, and expressed three pathogenic HMGCR variants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) in Hmgcr knockdown mouse myoblasts. Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown of hmgcr in Drosophila led to lethality. Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.

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“…NDUFAF7 is a human protein arginine methyltransferase resided in the mitochondrial matrix that forms the first nucleus of the peripheral arm and regulates mitochondrial complex I assembly and this function is associated with the risk of Alzheimer's disease 21,22 . Moreover, abnormal expression of NDUFAF7 could lead to mitochondrial dysfunction that might contribute to the development of myositis, especially IMNM 23,24 . POLR2J is a DNA repair gene that, through post‐transcriptional regulation, affects a variety of cancers, including rectal tumors and testicular germ cell tumors 25,26 .…”

Section: Discussionmentioning

confidence: 99%

“…21,22 Moreover, abnormal expression of NDUFAF7 could lead to mitochondrial dysfunction that might contribute to the development of myositis, especially IMNM. 23,24 POLR2J is a DNA repair gene that, through post-transcriptional regulation, affects a variety of cancers, including rectal tumors and testicular germ cell tumors. 25,26 CD99 is a transmembrane glycoprotein shown to be upregulated in various malignancies and is also crucial for peripheral immune responses.…”

Section: Gsea Of Key Genes In Imnmmentioning

confidence: 99%

Comprehensive transcriptomic analysis and machine learning reveal unique gene expression profiles in patients with immune‐mediated necrotizing myopathy

Liu,

Deng,

Guo

et al. 2023

The Journal of Gene Medicine

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BackgroundImmune‐mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterized by severe proximal weakness and muscle fiber necrosis, yet its pathogenesis remains unclear. So far, there are few bioinformatics studies on underlying pathogenic genes and infiltrating immune cell profiles of IMNM. Therefore, we aimed to characterize differentially expressed genes (DEGs) and infiltrating cells in IMNM muscle biopsy specimens, which may be useful for elucidating the pathogenesis of IMNM.MethodsThree datasets (GSE39454, GSE48280 and GSE128470) of gene expression profiling related to IMNM were obtained from the Gene Expression Omnibus database. Data were normalized, and DEG analysis was performed using the limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using clusterProfiler. The CIBERSORT algorithm was performed to identify infiltrating cells. Machine learning algorithm and gene set enrichment analysis (GSEA) were performed to find distinctive gene signatures and the underlying signaling pathways of IMNM.ResultsDEG analysis identified upregulated and downregulated in IMNM muscle compared to the gene expression levels of other groups. GO and KEGG analysis showed that the pathogenesis of IMNM was notable for the under‐representation of pathways that were important in dermatomyositis and inclusion body myositis. Three immune cells (M2 macrophages, resting dendritic cells and resting natural killer cells) with differential infiltration and five key genes (NDUFAF7, POLR2J, CD99, ARF5 and SKAP2) in patients with IMNM were identified through the CIBERSORT and machine learning algorithm. The GSEA results revealed that the key genes were remarkably enriched in diverse immunological and muscle metabolism‐related pathways.ConclusionsWe comprehensively explored immunological landscape of IMNM, which is indicative for the research of IMNM pathogenesis.

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Mitochondrial dysfunction in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) immune-mediated necrotising myopathy

Cited by 4 publications

References 11 publications

Clinicopathological and circulating cell‐free DNA profile in myositis associated with anti‐mitochondrial antibody

Clinicopathological and circulating cell‐free DNA profile in myositis associated with anti‐mitochondrial antibody

Effects of HMGCR deficiency on skeletal muscle development

Comprehensive transcriptomic analysis and machine learning reveal unique gene expression profiles in patients with immune‐mediated necrotizing myopathy

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