Integrated multi-omics approach reveals the role of SPEG in skeletal muscle biology including its relationship with myospryn complex
Integrated multi-omics approach reveals the role of SPEG in skeletal muscle biology including its relationship with myospryn complex
Abstract Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy. Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes. We identified that SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and SPEG deficiency results in myospryn complex abnormalities. In addition, transcriptional and protein profiles of SPEG-deficient muscle revealed defective mitochondrial function including aberrant accumulation of enlarged mitochondria on electron microscopy. Furthermore, SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites. On analyzing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction and peroxisome proliferator-activated receptors signaling, which may be due to defective triad and mitochondrial abnormalities. In summary, we have elucidated the critical role of SPEG in triad as it works closely with myospryn complex, phosphorylates JPH2 and RyR1, and demonstrated that its deficiency is associated with mitochondrial abnormalities. This study emphasizes the importance of using multi-omics techniques to comprehensively analyze the molecular anomalies of rare diseases. Synopsisbiorxiv;2023.04.24.538136v1/UFIG1F1ufig1We have previously linked mutations in SPEG (striated preferentially expressed protein) with a recessive form of centronuclear myopathy and/or dilated cardiomyopathy and have characterized a striated muscle-specific SPEG-deficient mouse model that recapitulates human disease with disruption of the triad structure and calcium homeostasis in skeletal muscles. In this study, we applied multi-omics approaches (interactomic, proteomic, phosphoproteomic, and transcriptomic analyses) in the skeletal muscles of SPEG-deficient mice to assess the underlying pathways associated with the pathological and molecular abnormalities.SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and its deficiency results in myospryn complex abnormalities.SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites.SPEGα and SPEGβ have different interacting partners suggestive of differential function.Transcriptome analysis indicates dysregulated pathways of ECM-receptor interaction and peroxisome proliferator-activated receptor signaling.Mitochondrial defects on the transcriptome, proteome, and electron microscopy, may be a consequence of defective calcium signaling.
Perrella Mark A.、Luo Shiyu、Agrawal Rohan、Beggs Alan H.、Liu Xiaoli、Schmitz-Abe Klaus、Meng Melissa、Moghadaszadeh Behzad、Agrawal Pankaj B.、Li Qifei、Lin Jasmine
Division of Pulmonary and Critical Care Medicine, Brigham and Women?ˉs Hospital, Harvard Medical School||Department of Pediatric Newborn Medicine, Brigham and Women?ˉs Hospital, Harvard Medical SchoolDivision of Newborn Medicine, Boston Children?ˉs Hospital, Harvard Medical School||Division of Genetics and Genomics, Boston Children?ˉs Hospital, Harvard Medical School||The Manton Center for Orphan Disease Research, Boston Children?ˉs Hospital, Harvard Medical School||Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children?ˉs Hospital, Jackson Health SystemDivision of Newborn Medicine, Boston Children?ˉs Hospital, Harvard Medical School||Division of Genetics and Genomics, Boston Children?ˉs Hospital, Harvard Medical School||The Manton Center for Orphan Disease Research, Boston Children?ˉs Hospital, Harvard Medical SchoolDivision of Genetics and Genomics, Boston Children?ˉs Hospital, Harvard Medical School||The Manton Center for Orphan Disease Research, Boston Children?ˉs Hospital, Harvard Medical SchoolDivision of Pulmonary and Critical Care Medicine, Brigham and Women?ˉs Hospital, Harvard Medical School||Department of Pediatric Newborn Medicine, Brigham and Women?ˉs Hospital, Harvard Medical SchoolDivision of Newborn Medicine, Boston Children?ˉs Hospital, Harvard Medical School||Division of Genetics and Genomics, Boston Children?ˉs Hospital, Harvard Medical School||The Manton Center for Orphan Disease Research, Boston Children?ˉs Hospital, Harvard Medical School||Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children?ˉs Hospital, Jackson Health SystemDivision of Genetics and Genomics, Boston Children?ˉs Hospital, Harvard Medical School||The Manton Center for Orphan Disease Research, Boston Children?ˉs Hospital, Harvard Medical SchoolDivision of Genetics and Genomics, Boston Children?ˉs Hospital, Harvard Medical School||The Manton Center for Orphan Disease Research, Boston Children?ˉs Hospital, Harvard Medical SchoolDivision of Newborn Medicine, Boston Children?ˉs Hospital, Harvard Medical School||Division of Genetics and Genomics, Boston Children?ˉs Hospital, Harvard Medical School||The Manton Center for Orphan Disease Research, Boston Children?ˉs Hospital, Harvard Medical School||Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children?ˉs Hospital, Jackson Health SystemDivision of Newborn Medicine, Boston Children?ˉs Hospital, Harvard Medical School||Division of Genetics and Genomics, Boston Children?ˉs Hospital, Harvard Medical School||The Manton Center for Orphan Disease Research, Boston Children?ˉs Hospital, Harvard Medical School||Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children?ˉs Hospital, Jackson Health SystemDivision of Newborn Medicine, Boston Children?ˉs Hospital, Harvard Medical School||Division of Genetics and Genomics, Boston Children?ˉs Hospital, Harvard Medical School||The Manton Center for Orphan Disease Research, Boston Children?ˉs Hospital, Harvard Medical School
基础医学分子生物学生理学
Perrella Mark A.,Luo Shiyu,Agrawal Rohan,Beggs Alan H.,Liu Xiaoli,Schmitz-Abe Klaus,Meng Melissa,Moghadaszadeh Behzad,Agrawal Pankaj B.,Li Qifei,Lin Jasmine.Integrated multi-omics approach reveals the role of SPEG in skeletal muscle biology including its relationship with myospryn complex[EB/OL].(2025-03-28)[2025-06-19].https://www.biorxiv.org/content/10.1101/2023.04.24.538136.点此复制
评论