FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21. FBXL21 interacts with TCAP in a circadian manner antiphasic to TCAP accumulation in skeletal muscle, and circadian TCAP oscillation is disrupted in Psttm mice with an Fbxl21 hypomorph mutation. GSK-3β phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3β inhibition or knockdown diminishes FBXL21-Cul1 complex formation and delays FBXL21-mediated TCAP degradation. Finally, Psttm mice show significant skeletal muscle defects, including impaired fiber size, exercise tolerance, grip strength, and response to glucocorticoid-induced atrophy, in conjunction with cardiac dysfunction. These data highlight a circadian regulatory pathway where a GSK-3β-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function.
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http://dx.doi.org/10.1016/j.celrep.2020.108140 | DOI Listing |
Pharmacol Res Perspect
December 2024
Protagenic Therapeutics Inc., New York, New York, USA.
Hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis response can result in anxiety and other neuropsychiatric disorders and effective therapeutics are needed to mitigate this maladaptive response. Here we examined the effects of Teneurin C-terminal Associated Peptide (TCAP)-1, a peptide known to inhibit corticotropin releasing factor (CRF)-mediated stress, on the physiological expression of stress, and whether the effects of TCAP-1 were dependent on the route of administration. We first examined whether subcutaneous administration of TCAP-1 influenced tube restraint stress-induced corticosterone (CORT) increases in both male mice and rats.
View Article and Find Full Text PDFTransl Psychiatry
October 2024
Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
J Mater Chem B
October 2024
National Engineering Research Centre for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, P. R. China.
The endowment of guided bone regeneration (GBR) membranes with the ability to activate the endogenous regenerative capability of bone to regenerate bone defects is of clinical significance. Herein we explored the preparation of the calcium compound (CC) (calcium sulfate (CaSL), calcium hydrophosphate (CaHP), or tricalcium phosphate (TCaP)) loaded ultrathin silk fibroin (SF)/gelatin (G) fibre membranes electrospinning as the GBR membranes to regenerate the calvarial bone defects. The experiments demonstrated that the CaSL-loaded ultrathin fibrous membranes could simulate optimally the bone remodelling microenvironment in comparison with the CaHP- and TCaP-loaded fibrous membranes, displaying the highest activity to regulate the migration, proliferation, and differentiation of mesenchymal stem cells (MSCs).
View Article and Find Full Text PDFBiochim Biophys Acta Mol Basis Dis
December 2024
TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China. Electronic address:
Telethonin/titin-cap (TCAP) encodes a Z-disc protein that plays important roles in sarcomere/T-tubule interactions, stretch-sensing and signaling. Mutations in TCAP are associated with muscular dystrophy and cardiomyopathy; however, the complete etiology and its roles in myocardial infarction and regeneration are not fully understood. Here, we generated tcap gene knockout zebrafish with CRISPR/Cas9 technology and observed muscular dystrophy-like phenotypes and abnormal mitochondria in skeletal muscles.
View Article and Find Full Text PDFBMC Cardiovasc Disord
August 2024
First Department of Cardiology, The Affiliated Guangdong Second Provincial General Hospi-tal of Jinan University, NO. 466, Xingang Middle Road, Haizhu District, Guangzhou City, China.
Background: Heart failure (HF), which is caused by cardiac overload and injury, is linked to significant mortality. Writers of RNA modification (WRMs) play a crucial role in the regulation of epigenetic processes involved in immune response and cardiovascular disease. However, the potential roles of these writers in the immunological milieu of HF remain unknown.
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