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

doi:10.1016/j.ebiom.2018.04.024

. 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

Lisa M Walter¹, Marc-Olivier Deguise², Katharina E Meijboom³, Corinne A Betts³, Nina Ahlskog³, Tirsa L E van Westering³, Gareth Hazell³, Emily McFall², Anna Kordala³, Suzan M Hammond³, Frank Abendroth⁴, Lyndsay M Murray⁵, Hannah K Shorrock⁵, Domenick A Prosdocimo⁶, Saptarsi M Haldar⁷, Mukesh K Jain⁶, Thomas H Gillingwater⁵, Peter Claus¹, Rashmi Kothary², Matthew J A Wood³, Melissa Bowerman⁸

Affiliations

¹ Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany; Center of Systems Neuroscience, Hannover, Germany.
² Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada; Department of Medicine and Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
³ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
⁴ Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom.
⁵ Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom; Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
⁶ Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA.
⁷ Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA; Department of Medicine, Division of Cardiology University of California, San Francisco, CA, USA.
⁸ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. Electronic address: m.bowerman@keele.ac.uk.

PMID: 29735415
PMCID: PMC6013932
DOI: 10.1016/j.ebiom.2018.04.024

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

Lisa M Walter et al. EBioMedicine. 2018 May.

. 2018 May:31:226-242.

doi: 10.1016/j.ebiom.2018.04.024. Epub 2018 May 4.

Authors

Affiliations

¹ Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany; Center of Systems Neuroscience, Hannover, Germany.
² Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada; Department of Medicine and Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
³ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
⁴ Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom.
⁵ Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom; Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
⁶ Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA.
⁷ Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA; Department of Medicine, Division of Cardiology University of California, San Francisco, CA, USA.
⁸ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. Electronic address: m.bowerman@keele.ac.uk.

PMID: 29735415
PMCID: PMC6013932
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 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.

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

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Figures

**Fig. 1**
Dysregulation of the GC-KLF15-BCAA pathway in severe SMA mice and human SMA patients. a. qPCR analysis of *GRα* mRNA in four different skeletal muscles (*triceps brachii* (triceps), *gastrocnemius* (gastro), *tibialis anterior* (TA) and *quadriceps femoris* (quad)) of post-natal day (P) 2 *Smn*^−/−*;SMN2* mice compared to WT animals. Data represent mean ± SD; n = 3–4 animals per group; two-tailed *t-test*; triceps: p = 0.0113; gastro: p = 0.0487; TA: p = 0.0176; quad: p = 0.0042. b. qPCR analysis of *GRβ* mRNA in four different skeletal muscles of P7 *Smn*^−/−*;SMN2* mice compared to WT animals. Data represent mean ± SD; n = 3–4 animals per group; two-tailed *t-test*; triceps: p = 0.0075; gastro: p = 0.004; TA: p = 0.0352; quad: p = 0.0008. c. qPCR analysis of *Klf15* mRNA in four different skeletal muscles of *Smn*^−/−*;SMN2* mice compared to WT animals at P0, P2, P5, P7 and P10. Data represent mean ± SD; n = 3–4 animals per group; two-way ANOVA; ***p < 0.001, ****p < 0.0001. d. BCAA metabolism effector genes (mRNA) dysregulated in triceps of P2 and P7 *Smn*^−/−*;SMN2* animals compared to WT mice. Data represent fold up- or downregulation with p > 0.05. e. qPCR analysis of *Klf15* mRNA in heart and liver of P2 and P7 *Smn*^−/−*;SMN2* mice compared to WT animals. Data represent mean ± SD, n = 3–4 animals per group, two-way ANOVA; **p < 0.01, ****p < 0.0001. f. Quantification of total S6 K1/total protein in triceps of P7 *Smn*^−/−*;SMN2* mice compared to healthy littermates. Total protein was visualized with Fast Green (FG) stain. Images are representative immunoblots. Data represent mean ± SD, n = 5–7 animals per group, two-tailed *t-test*; p = 0.0325. g. Quantification of phosphorylated (p)-S6 and total S6/total protein in triceps of P7 *Smn*^−/−*;SMN2* mice compared to healthy littermates. Total protein was visualized with Fast Green (FG) stain. Images are representative immunoblots. Data represent mean ± SD, n = 5–7 animals per group, two-tailed *t-test*; p-S6: p = 0.0024; total S6: p = 0.0024. h. Quantification of KLF15 protein/total protein in human gastrocnemius muscle samples from non-SMA control individuals and SMA Type I-III patients.

**Fig. 2**
Circadian rhythmicity of the GC-KLF15-BCAA axis is dysregulated in severe SMA mice. a. Corticosterone levels in serum of post-natal day (P) 2 and P7 *Smn*^−/−*;SMN2* mice compared to healthy control littermates at the Zeitgeber time (ZT) 5 and ZT17. Data represent mean ± SD; n = 3–4 animals per group, two-way ANOVA; *p < 0.05 b. qPCR analysis of diurnal expression of *GRα* mRNA in the *tibialis anterior* (TA) of P2 and P7 *Smn*^−/−*;SMN2* mice compared to healthy controls. c. qPCR analysis of diurnal expression of *GRβ* mRNA in the TA of P2 and P7 *Smn*^−/−*;SMN2* mice compared to healthy controls. d. qPCR analysis of diurnal expression of *Klf15* mRNA in the TA of P2 and P7 *Smn*^−/−*;SMN2* mice compared to healthy controls. **b-d:** Data represent mean ± SD; n = 3–5 animals per group, two-way ANOVA; *p < 0.05, **p < 0.01, ****p < 0.0001; # indicates cycling ZT1 data is duplicated. e. Levels of the BCAAs valine, leucine and isoleucine in triceps of P2 and P7 *Smn*^−/−*;SMN2* and healthy controls. f. Levels of the BCAAs in serum of P2 and P7 *Smn*^−/−*;SMN2* and healthy control animals. **e–f:** each data point represents the pooling of 5–15 animals.

**Fig. 3**
Schematic summarizing the activity of the glucocorticoid (GC)- glucocorticoid receptor (GR, α and β)-Klf15-BCAT2-branched-chain amino acid (BCAA) signaling cascade in normal muscle (a), pre-symptomatic muscle from *Smn*^−/−*;SMN2* SMA mice (b) and symptomatic muscle from *Smn*^−/−*;SMN2* SMA mice (c).

**Fig. 4**
Prednisolone treatment improves disease phenotypes in severe SMA mice. qPCR analysis of **(a)***Nr3c1*, (b) *GRα* and *GRβ* (c) *Klf15* and (d) *Bcat2* mRNAs in *tibialis anterior* (TA) muscle of post-natal day (P) 2 and P7 untreated and prednisolone-treated *Smn*^−/−*;SMN2* mice and control littermates. **a-d:** Data represent mean ± SD; n = 3–4 animals per group; two-way ANOVA; *p < 0.05, **p < 0.01, ****p < 0.0001; ns = not significant. e. Weight curves of prednisolone-treated *Smn*^−/−*;SMN2* mice vs. untreated animals. Data represent mean ± SD; n = 10–16 animals per group; *p < 0.05, **p < 0.01. f. Lifespan of prednisolone-treated *Smn*^−/−*;SMN2* mice vs. untreated animals. Data represent Kaplan-Meier curves; n = 10–16 animals per group; Log-rank (Mantel-Cox) test; p = 0.0009. g. Weight curves of prednisolone-treated healthy controls vs. untreated animals. Data represent mean ± SD; n = 9–18 animals per group; ****p < 0.0001.

**Fig. 5**
Dysregulation of the GC-KLF15-BCAA pathway in intermediate SMA mice and prednisolone-induced phenotypic improvements. a. qPCR analysis of *Klf15* mRNA in *tibialis anterior* (TA) of *Smn*^2B/− mice compared to WT animals at different ages (post-natal day (P) 0, P2, P4, P11 and P19). Data represent mean ± SD; n = 4 animals per group; two-way ANOVA; *p < 0.05, **p < 0.01, ***p < 0.001; ns = not significant. b. BCAA metabolism effector genes (mRNA) dysregulated in TAs of pre- and symptomatic *Smn*^2B/− mice compared to WT animals. Data represent fold up- or downregulation with p > 0.05. c. Venn diagram demonstrating the number of upregulated BCAA metabolism effectors in TAs of symptomatic *Smn*^−/−*;SMN2* and *Smn*^2B/− mice. d. Weight curves of prednisolone-treated *Smn*^2B/− mice vs. saline-treated animals. Data represent mean ± SD; n = 10–12 animals per group; two-way ANOVA; *p < 0.05; ns = not significant. e. Lifespan of prednisolone-treated *Smn*^2B/− mice vs. saline-treated animals. Data represent Kaplan-Meier curves; n = 10–12 animals per group; Log-rank (Mantel-Cox) test; p < 0.0001. f. Weight curves of *Smn*^2B/+ mice treated with prednisolone or saline. Data represent mean ± SD; n = 7–10 animals per group; two-way ANOVA; ns = not significant.

**Fig. 6**
Prednisolone treatment improves neuromuscular phenotypes in severe SMA mice. *Smn*^−/−*;SMN2* mice and healthy littermates were treated with 5 mg/kg prednisolone every second day beginning from P0. qPCR analysis of (a) *MuRF-1*, (b) *atrogin1*, (c) *MyoD*, (d) *myogenin* and (e) *parvalbumin* mRNAs in triceps of P7 *Smn*^−/−*;SMN2* mice and healthy littermates treated with prednisolone compared to untreated animals. **a-e:** Data represent mean ± SD; n = 3–4 animals per group; two-way ANOVA; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < .0001; ns = not significant. f. Motor endplate area in TAs of untreated and prednisolone-treated P7 *Smn*^−/−*;SMN2* mice and healthy littermates. Data represent scatter plot ± SD; n = 424–711 endplates from 4 animals per group; one-way ANOVA; ****p < 0.0001; ns = not significant. g. Quantitative analysis of motor endplate morphology (plaque-like or perforated) in TAs of untreated and prednisolone treated P7 *Smn*^−/−*;SMN2* mice and healthy littermates. Representative image of endplates where arrow indicates perforated and arrowhead indicates plaque-like. h. Quantitative analysis of the innervation status of motor endplates in TAs of untreated and prednisolone-treated P7 *Smn*^−/−*;SMN2* mice and healthy control littermates. Representative image of NMJs from untreated and prednisolone-treated *Smn*^−/−*;SMN2* mice where arrowhead indicates incomplete innervation. **g-h.** Data represent mean ± SD; n = 4 animals per group; two-way ANOVA; **p < 0,01; ns = not significant.

**Fig. 7**
Synergistic effects of *Klf15* overexpression and prednisolone on disease phenotypes of severe SMA mice. a. qPCR analysis of *Klf15* mRNA in skeletal muscle (quadriceps) from post-natal day (P) 2 and 7 *Smn*^−/−*;SMN2*, *Smn*^+/−*;SMN2*, *Smn*^−/−*;SMN2;KLF15 MTg* and *Smn*^+/−*;SMN2;KLF15* MTg mice. Data represent mean ± SD; n = 3–8 animals per group; two-way ANOVA; **p < 0.01, ***p < 0.001, ****p < 0.0001. qPCR analysis of (b) *Nr3c1*, (c) *GRα*, (d) *GRβ*, (e) *Bcat2*, (f) *atrogin-1*, (g) *MuRF-1*, (h) *Myod*, (i) *myogenin* and (j) *parvalbumin* mRNAs in quadriceps of P7 *Smn*^−/−*;SMN2*, *Smn*^+/−*;SMN2*, *Smn*^−/−*;SMN2;KLF15 MTg* and *Smn*^+/−*;SMN2;KLF15* MTg mice. **b-j**: Data represent mean ± SD; n = 6–8 animals per group; one-way ANOVA; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, ns = not significant. k. Lifespan of untreated and prednisolone-treated *Smn*^−/−*;SMN2* and *Smn*^−/−*;SMN2;KLF15 MTg* mice. Data represent Kaplan-Meier curves; n = 11–36 animals per group; Log-rank test; *p < 0.05, ***p < 0.001. l. Weight curves of untreated and prednisolone-treated *Smn*^−/−*;SMN2* and *Smn*^−/−*;SMN2;KLF15 MTg* mice. Data represent mean ± SD; n = 7–10 animals per group; two-way ANOVA; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. m. Weight curves of untreated and prednisolone-treated *Smn*^+/−*;SMN2* and *Smn*^+/−*;SMN2;KLF15 MTg* mice. Data represent mean ± SD; n = 7–10 animals per group; two-way ANOVA; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

**Fig. 8**
BCAA supplementation improves disease phenotypes of severe SMA mice. *Smn*^−/−*;SMN2* mice and healthy controls were treated with BCAAs (1.5 mg/kg) starting at P5. a. Weight curves of BCAA-treated *Smn*^−/−*;SMN2* mice vs. untreated animals. Data represent mean ± SD; n = 12–16 animals per group; two-way ANOVA; *p < 0.05, ***p < 0.001, ****p < 0.0001. b. Lifespan of BCAA-treated *Smn*^−/−*;SMN2* mice vs. untreated animals. Data represent Kaplan-Meier curves; n = 10–16 animals per group; Log-rank (Mantel-Cox) test; p = 0.0159. c. Weight curves of BCAA-treated healthy controls vs. untreated animals. Data represent mean ± SD; n = 14–18 animals per group; two-way ANOVA; *p < 0.05, **p < 0.01. qPCR analysis of (d) *Nr3c1*, (e) *GRα*, (f) *GRβ*, (g) *Klf15*, (h) *Bcat2*, (i) *MuRF-1*, (j) *atrogin-1*, (k) *MyoD*, (l) *myogenin* and (m) parvalbumin mRNAs expression in triceps of BCAA-treated P7 *Smn*^−/−*;SMN2* mice and healthy controls compared to untreated animals. **d-m:** Data represent mean ± SD; n = 3–4 animals per group; two-way ANOVA; **p < 0.01; ns = not significant. n. Motor endplate area in TAs of BCAA-treated P7 *Smn*^−/−*;SMN2* mice and healthy littermates compared to untreated animals. Data represent scatter plot ± SD; n = 198–324 endplates from 4 animals per group; one-way ANOVA; **p < 0.01, ****p < 0.0001; ns = not significant. o. Motor endplate morphology (plaque-like or perforated) in TAs of BCAA-treated P7 *Smn*^−/−*;SMN2* mice and healthy controls compared to untreated animals. Representative images of endplates from untreated and BCAA-treated *Smn*^−/−*;SMN2* mice and healthy littermates. p. Innervation status of motor endplates in TAs of BCAA-treated P7 *Smn*^−/−*;SMN2* mice and healthy controls compared to untreated animals. Representative images of NMJs from untreated and BCAA-treated *Smn*^−/−*;SMN2* mice. **o-p**. Data represent mean ± SD; n = 4 animals per group; two-way ANOVA; *p < 0.05, ***p < 0.001; ns = not significant.

**Fig. 9**
Schematic summarizing the aberrant effectors of the glucocorticoid (GC)-Klf15-branched-chain amino acid (BCAA) signaling cascade targeted by a pre-symptomatic administration of prednisolone (a) and symptomatic BCCA supplementation (b) and the observed effects on molecular, histological and behavioral disease phenotypes.

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References

1. Desvergne B., Michalik L., Wahli W. Transcriptional regulation of metabolism. Physiol. Rev. 2006;86 - PubMed
1. Gray, S., Feinberg, M.W., Hull, S., Kuo, C.T., Watanabe, M., Sen, S., DePina, A., Haspel, R., Jain, M.K., 2002. The Krü ppel-like Factor KLF15 Regulates the Insulin-sensitive Glucose Transporter GLUT4*. https://doi.org/10.1074/jbc.M201304200 - DOI - PubMed
1. Haldar S.M., Jeyaraj D., Anand P., Zhu H., Lu Y., Prosdocimo D.A. Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation. Proc. Natl. Acad. Sci. U. S. A. 2012;109:6739–6744. - PMC - PubMed
1. Gray S., Wang B., Orihuela Y., Hong E.-G., Fisch S., Haldar S. Regulation of gluconeogenesis by Krüppel-like factor 15. Cell Metab. 2007;5:305–312. - PMC - PubMed
1. Jeyaraj D., Scheer F.A.J.L., Ripperger J.A., Haldar S.M., Lu Y., Prosdocimo D.A. Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab. 2012;15:311–323. - PMC - PubMed

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[1] Desvergne B., Michalik L., Wahli W. Transcriptional regulation of metabolism. Physiol. Rev. 2006;86 - PubMed

[2] Desvergne B., Michalik L., Wahli W. Transcriptional regulation of metabolism. Physiol. Rev. 2006;86 - PubMed

[3] Gray, S., Feinberg, M.W., Hull, S., Kuo, C.T., Watanabe, M., Sen, S., DePina, A., Haspel, R., Jain, M.K., 2002. The Krü ppel-like Factor KLF15 Regulates the Insulin-sensitive Glucose Transporter GLUT4*. https://doi.org/10.1074/jbc.M201304200 - DOI - PubMed

[4] Gray, S., Feinberg, M.W., Hull, S., Kuo, C.T., Watanabe, M., Sen, S., DePina, A., Haspel, R., Jain, M.K., 2002. The Krü ppel-like Factor KLF15 Regulates the Insulin-sensitive Glucose Transporter GLUT4*. https://doi.org/10.1074/jbc.M201304200 - DOI - PubMed

[5] Haldar S.M., Jeyaraj D., Anand P., Zhu H., Lu Y., Prosdocimo D.A. Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation. Proc. Natl. Acad. Sci. U. S. A. 2012;109:6739–6744. - PMC - PubMed

[6] Haldar S.M., Jeyaraj D., Anand P., Zhu H., Lu Y., Prosdocimo D.A. Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation. Proc. Natl. Acad. Sci. U. S. A. 2012;109:6739–6744. - PMC - PubMed

[7] Gray S., Wang B., Orihuela Y., Hong E.-G., Fisch S., Haldar S. Regulation of gluconeogenesis by Krüppel-like factor 15. Cell Metab. 2007;5:305–312. - PMC - PubMed

[8] Gray S., Wang B., Orihuela Y., Hong E.-G., Fisch S., Haldar S. Regulation of gluconeogenesis by Krüppel-like factor 15. Cell Metab. 2007;5:305–312. - PMC - PubMed

[9] Jeyaraj D., Scheer F.A.J.L., Ripperger J.A., Haldar S.M., Lu Y., Prosdocimo D.A. Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab. 2012;15:311–323. - PMC - PubMed

[10] Jeyaraj D., Scheer F.A.J.L., Ripperger J.A., Haldar S.M., Lu Y., Prosdocimo D.A. Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab. 2012;15:311–323. - PMC - PubMed

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

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

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