期刊
EBIOMEDICINE
卷 31, 期 -, 页码 226-242出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2018.04.024
关键词
Spinal muscular atrophy; KLF15; Glucocorticoids; Branched-chain amino acids; Metabolism; Therapy
资金
- SMA Trust
- SMA Angels Charity
- Gwendolyn Strong Foundation
- FightSMA
- Association Francaise contre les Myopathies [20544]
- Cure SMA/Families of SMA Canada
- Canadian Institutes of Health Research (CIHR) [MOP-130279]
- Erasmus+ program scholarship
- Muscular Dystrophy UK
- Frederick Banting and Charles Best CIHR Doctoral Research Award
- MRC [MC_U105178803, MR/L013142/1] Funding Source: UKRI
The circadian glucocorticoid-Kruppel-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 Smn(2B/-) 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. (C) 2018 The Authors. Published by Elsevier B.V.
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