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The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn-/-;SMN2 and Smn2B/- mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling.
Pubmed ID: 29735415 RIS Download
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Commercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.
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View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsMus musculus with name FVB/NJ from IMSR.
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets KLF15
View all literature mentionsThis unknown targets Mouse IgG2b (??2b)
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis polyclonal targets Phospho-S6 Ribosomal Protein (Ser235/236)
View all literature mentionsThis monoclonal targets S6 Ribosomal Protein
View all literature mentionsThis monoclonal targets p70 S6 Kinase
View all literature mentionsMus musculus with name FVB.Cg-Smn1tm1Hung Tg(SMN2)2Hung/J from IMSR.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on April 12,2023. Matlab code for two-factor (location and year) analysis-of-variance model for the calculation of climate anomalies, in which the reference interval is specified as the full length of the dataset. This scheme avoids the affects of shorter (e.g. 1961-1990) reference intervals on the temporal evolution of the spatial standard deviation of climate anomalies. Data files provided.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets KLF15
View all literature mentionsThis unknown targets Mouse IgG2b (??2b)
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis polyclonal targets Phospho-S6 Ribosomal Protein (Ser235/236)
View all literature mentionsThis monoclonal targets S6 Ribosomal Protein
View all literature mentionsThis monoclonal targets p70 S6 Kinase
View all literature mentionsMus musculus with name FVB.Cg-Smn1tm1Hung Tg(SMN2)2Hung/J from IMSR.
View all literature mentionsThis monoclonal targets p70 S6 Kinase
View all literature mentionsThis polyclonal targets Phospho-S6 Ribosomal Protein (Ser235/236)
View all literature mentionsThis monoclonal targets S6 Ribosomal Protein
View all literature mentionsThis unknown targets Mouse IgG2b (??2b)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets KLF15
View all literature mentionsThis polyclonal targets IgG
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