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The neuromuscular junction (NMJ) performs the crucial function of controlling skeletal muscle contraction. NMJ formation depends on the Agrin/Lrp4/MuSK/Dok-7 signaling pathway. However, signaling downstream of Dok-7 remains incompletely understood. Here we used the phosphorylated iTRAQ technique to identify downstream molecules of Dok-7 in muscle cells. We found 16 Agrin/Dok-7-mediated serine/threonine phosphorylated proteins, and we validated the role of one phosphorylated protein, JPH2, in regulating AChR clustering. Our phosphoproteomics analysis sheds light on the underappreciated signaling network downstream of Agrin/Dok-7, thus providing new clues for understanding pathogenesis and developing treatment methods for neuromuscular diseases.
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http://dx.doi.org/10.1002/1873-3468.70050 | DOI Listing |
Am J Physiol Cell Physiol
September 2025
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC.
Cachexia, the loss of skeletal muscle mass and function with cancer, contributes to reduced life quality and worsened survival. Skeletal muscle fibrosis leads to disproportionate muscle weakness; however, the role of infiltrating immune cells and fibro-adipogenic progenitors (FAPs) in cancer-induced muscle fibrosis is not well understood. Using the C26 model of cancer cachexia, we sought to examine the changes to skeletal muscle immune cells and FAPs which contribute to excessive extracellular matrix (ECM) collagen deposition.
View Article and Find Full Text PDFPLoS One
September 2025
Department of Cardiac Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Background: Cardiac ischemia reperfusion (I/R) injury is a serious consequence of reperfusion therapy for myocardial infarction (MI). Peptidylarginine deiminase 4 (PAD4) is a calcium-dependent enzyme that catalyzes the citrullination of proteins. In previous studies, PAD4 inhibition protected distinct organs from I/R injury by preventing the formation of neutrophil extracellular traps (NETs) and attenuating inflammatory responses.
View Article and Find Full Text PDFMol Biol Cell
September 2025
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine Basic Sciences, Nashville, TN, USA.
Cardiac sarcomere assembly is a highly orchestrated process requiring integration between intracellular contractile machinery and extracellular adhesions. While α-actinin-2 (ACTN2) is well known for its structural role at the cardiac Z-disc, the sarcomere border, the function of the "non-muscle" paralog α-actinin-1 (ACTN1) in cardiac myocytes remains unclear. Using human induced pluripotent stem cell-derived cardiac myocytes (hiCMs), we demonstrate that siRNA-mediated depletion of ACTN1 disrupts sarcomere assembly, and that exogenous re-introduction of ACTN1 but not ACTN2 restores assembly, revealing non-redundant functions.
View Article and Find Full Text PDFMol Biol Rep
September 2025
Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766-1854, USA.
Regenerative cardiology has emerged as a novel strategy to improve cardiac healing following ischemic injury. While stem-cell-mediated cardiac regeneration has garnered much attention as a promising strategy, its value remains debated owing to the lack of ideal stem cell source candidates. Resident/endogenous cardiac-derived stromal cells (CSCs) exhibit superior therapeutic potential due to their innate abilities to differentiate into cardiac cells, especially cardiomyocytes (CM).
View Article and Find Full Text PDFNeuropathol Appl Neurobiol
October 2025
Division of Rheumatology and Systemic Inflammatory Diseases, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Aims: Sarcoid myopathy (SaM) is characterised by granulomatous myositis (GM) and can overlap with inclusion body myositis (IBM), a late-onset chronic idiopathic inflammatory myopathy with a still enigmatic pathogenesis. As GM can occur in different clinical contexts, we aimed to examine the histomorphologic features and gene expression profiles in cases of definite SaM that may inform diagnostic and therapeutic considerations.
Methods: We performed a multidimensional characterisation of muscle biopsy specimens from patients with 'pure SaM' (n=17), SaM with concomitant IBM (SaM-IBM) (n=2), including histopathologic and ultrastructural analysis in addition to quantitative real-time polymerase chain reaction.