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

Lisa Walter ,Domenick A Prosdocimo,Katharina E Meijboom,Thomas H Gillingwater,Mukesh K Jain,Suzan M Hammond,Anna Kordala,Rashmi Kothary,Emily Mcfall,Frank Abendroth,Lyndsay M Murray,Nina Ahlskog,Peter Claus,Saptarsi M Haldar,Hannah K Shorrock,Gareth Hazell,Matthew Wood ,Corinne Betts ,Van Westering Tle ,Marc‐Olivier Deguise ,Mélissa Bowerman

doi:10.1016/j.ebiom.2018.04.024

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.

Highlights

Transcriptional regulation is one of the main control mechanisms of metabolic processes [1]
We examined the expression profile of Klf15 mRNA during disease progression and found the same pattern in all four muscles: decreased levels in P2 and increased levels in P7 Smn−/−;SMN2 mice compared to wild type (WT) animals (Fig. 1c)
To assess if aberrant circadian expression of Klf15 mRNA was specific to skeletal muscle, we evaluated its rhythmicity in various metabolic tissues (white adipose tissue (WAT), brown adipose tissue (BAT), liver and heart) and spinal cord (SC) from P2 and P7 Smn−/−;SMN2 mice and control littermates (Supplementary Fig. 6)

Summary

Introduction

Transcriptional regulation is one of the main control mechanisms of metabolic processes [1]. Humans have at least one copy of the highly homologous SMN2 gene, which generates a low amount of functional protein that allows for embryonic development, while not being sufficient for complete rescue in the event of SMN1 loss. This is due to a nucleotide transition in SMN2 that favors alternative splicing of exon 7 and production of a non-functional truncated protein [19,21,22]. Whilst several cellular functions for SMN have been defined [23,24,25], it remains elusive why a lack of the ubiquitously expressed SMN results in the canonical SMA phenotype

Methods

Results

Conclusion