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

Walter, Lisa M.; Deguise, Marc-Olivier; Meijboom, Katharina E.; Betts, Corinne A.; Ahlskog, Nina; van Westering, Tirsa L.E.; Hazell, Gareth; McFall, Emily; Kordala, Anna; Hammond, Suzan M.; Abendroth, Frank; Murray, Lyndsay M.; Shorrock, Hannah K.; Prosdocimo, Domenick A.; Haldar, Saptarsi M.; Jain, Mukesh K.; Gillingwater, Thomas H.; Claus, Peter; Kothary, Rashmi; Wood, Matthew J.A.; Bowerman, Melissa

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


Authors

Lisa M. Walter

Marc-Olivier Deguise

Katharina E. Meijboom

Corinne A. Betts

Nina Ahlskog

Tirsa L.E. van Westering

Gareth Hazell

Emily McFall

Anna Kordala

Suzan M. Hammond

Frank Abendroth

Lyndsay M. Murray

Hannah K. Shorrock

Domenick A. Prosdocimo

Saptarsi M. Haldar

Mukesh K. Jain

Thomas H. Gillingwater

Peter Claus

Rashmi Kothary

Matthew J.A. Wood



Abstract

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.

Acceptance Date Apr 26, 2018
Publication Date May 1, 2018
Journal EBioMedicine
Publisher Elsevier
Pages 226-242
DOI https://doi.org/10.1016/j.ebiom.2018.04.024
Keywords spinal muscular atrophy, KLF15, glucocorticoids, branched-chain amino acids, metabolism, therapy
Publisher URL https://doi.org/10.1016/j.ebiom.2018.04.024

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