Dataset Information

Molecular Insights into Central Core Disease: Proteomic Signatures and Potential Therapeutic Biomarkers in RYR1 I4895T Mice

ABSTRACT: Central Core Disease (CCD) is a congenital myopathy, predominantly caused by mutations in the gene encoding for ryanodine receptor type-1(RYR1), the intracellular Ca2+ release channel embedded in skeletal muscle sarcoplasmic reticulum membrane. One of the most common RYR1 mutations associated to CCD is represented by the I4898T. Unfortunately, there are no approved therapies for CCD and for other myopathies caused by mutations in gene. This study aims to perform a top-down differential proteomic analysis on soleus tissue samples from wild-type mice (WT) and heterozygous knock mice carrying the- I4895T (IT) mutation in RyR1, to investigate pathogenic mechanisms and molecular pathways involved in this myopathy and to shed light on new potential biomarkers useful for future therapies. Proteomic analysis revealed 50 dysregulated protein species and multivariate analysis shows that IT mice exhibit a distinct proteomic signature compared to WT mice, characterized by alterations in proteins associated with contractile and structural dysfunction, metabolism, and stress response. In particular, a significant increase in myosin fragments was observed in IT mice, likely due to muscle breakdown. In contrast, myotilin was downregulated, suggesting a weakening of muscle cytoskeletal structure. There was a notable downregulation of proteins involved in glycolysis and TCA cycle; conversely, there was an increase in proteins related to anaerobic glycolysis, suggesting a shift from aerobic to anaerobic glycolysis. Furthermore, proteins involved in fatty acid beta-oxidation and oxidative phosphorylation were also found to be up regulated in IT mice, indicating an attempt by the muscle to maximize energy production. Finally, we found a significant decrease in PGC1α, which could serve as potential target-therapy biomarker in CCD.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Soleus

DISEASE(S): Congenital Myopathy 1a

SUBMITTER: Lorenza Vantaggiato

LAB HEAD: Luca Bini

PROVIDER: PXD069980 | Pride | 2025-12-22

REPOSITORIES: Pride

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Molecular Insights into Central Core Disease: Proteomic Signatures and Potential Therapeutic Biomarkers in RYR1 I4895T Mice.

Vantaggiato Lorenza L Shaba Enxhi E Fiore Federica F Rossi Daniela D Sorrentino Vincenzo V Bini Luca L Landi Claudia C

International journal of molecular sciences 20251126 23

Central Core Disease (CCD) is a congenital myopathy predominantly caused by mutations in the gene encoding ryanodine receptor type-1 (RYR1), the intracellular Ca2+ release channel embedded in the skeletal muscle sarcoplasmic reticulum membrane. The I4898T mutation represents one of the most common RYR1 mutations associated with CCD. Unfortunately, there are no approved therapies for CCD or for other myopathies caused by mutations in this gene. This study aims to perform a top-down dif ...[more]

PMID: 41373610

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Project description:Severe myopathic events occur in 0.1-0.5% of patients taking statins. Although genetic association studies have identified some possibly associated gene loci, these have not been reproducible in additional studies with independent patient cohorts. A more reasonable explanation for susceptibility to statin-induced myopathy is the presence of rare pathogenic variants in genes important for skeletal muscle structure and function. In support of this, we have previously reported an increased incidence of pathogenic variants in genes causing metabolic myopathies in patients with statin-induced myopathy (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">Vladutiu et al.</a>,2006). We also reported a patient with statin myopathy who had an RYR1 variant known to be causative of malignant hyperthermia susceptibility (MHS) (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">Vladutiu et al.</a>, 2011). There are a number of genes associated with metabolic myopathies triggered by various factors such as extreme exercise, fasting, extremes in temperature, viral infection and exposure to volatile anesthetics. In addition, many of the genes causing congenital myopathies, myofibrillar myopathies and muscular dystrophies have overlapping phenotypes with these genes. We propose that statins act as an additional trigger inducing myopathic symptoms and many patients with severe statin-induced myopathy have causative genetic variants within similar genes associated with MHS and congenital myopathy. We have analyzed the resultant data using a disease model in which rare pathogenic variants, possibly within multiple genes, are causative of statin-induced myopathy. In this study, we have identified potentially causative genetic variants in greater than 50% of the statin-induced myopathy cases and in particular, rare and possibly pathogenic in the RYR1 and CACNA1S genes were present in 25% of the patient samples studied. Vladutiu, G. D., Simmons, Z., Isackson, P.J., Tarnopolsky, M., Peltier, W.L., Barboi, A.C., Sripathi, N., Wortmann, R.L., Phillips, P.S., (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">2006</a>). "Genetic risk factors associated with lipid-lowering drug-induced myopathies." Muscle Nerve 34: 153-162. Vladutiu, G. D., Isackson, P.J., Kaufman, K., Harley, J.B., Cobb, B., Christopher-Stine, L., Wortmann, R.L, (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">2011</a>). "Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies." Mol Genet Metab 104: 167-173.

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