Send to

Choose Destination
EBioMedicine. 2018 May;31:226-242. doi: 10.1016/j.ebiom.2018.04.024. Epub 2018 May 4.

Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice.

Author information

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany; Center of Systems Neuroscience, Hannover, Germany.
Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada; Department of Medicine and Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom.
Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom; Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA.
Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA; Department of Medicine, Division of Cardiology University of California, San Francisco, CA, USA.
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. Electronic address:


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.


Branched-chain amino acids; Glucocorticoids; KLF15; Metabolism; Spinal muscular atrophy; Therapy

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center