Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome

Scala, Rosa; Maqoud, Fatima; Zizzo, Nicola; Passantino, Giuseppe; Mele, Antonietta; Camerino, Giulia Maria; McClenaghan, Conor; Harter, Theresa M.; Nichols, Colin G.; Tricarico, Domenico

doi:10.3390/cells10071791

Open AccessArticle

Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome

by

Rosa Scala

^1,†,

Fatima Maqoud

^1,†,

Nicola Zizzo

^2,†

,

Giuseppe Passantino

²

,

Antonietta Mele

¹,

Giulia Maria Camerino

¹,

Conor McClenaghan

³,

Theresa M. Harter

³,

Colin G. Nichols

³ and

Domenico Tricarico

^1,*

¹

Section of Pharmacology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy

²

Section of Veterinary Pathology and Comparative Oncology, Department of Veterinary Medicine, University of Bari “Aldo Moro”, 70121 Bari, Italy

³

Center for the Investigation of Membrane Excitability Diseases, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110-1010, USA

^*

Author to whom correspondence should be addressed.

^†

These authors contributed to the work equally.

Cells 2021, 10(7), 1791; https://doi.org/10.3390/cells10071791

Submission received: 21 May 2021 / Revised: 12 July 2021 / Accepted: 13 July 2021 / Published: 15 July 2021

(This article belongs to the Special Issue Skeletal Muscle Ion Channels in Health and Diseases)

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Abstract

(1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in the ABCC9 and KCNJ8 genes, which encode ATP-sensitive K⁺ (KATP) channel subunits SUR2 and Kir6.1, respectively. Most CS patients have mutations in SUR2, the major component of skeletal muscle KATP, but the consequences of SUR2 GOF in skeletal muscle are unknown. (2) Methods: We performed in vivo and ex vivo characterization of skeletal muscle in heterozygous SUR2[A478V] (SUR2^wt/AV) and homozygous SUR2[A478V] (SUR2^AV/AV) CS mice. (3) Results: In SUR2^wt/AV and SUR2^AV/AV mice, forelimb strength and diaphragm amplitude movement were reduced; muscle echodensity was enhanced. KATP channel currents recorded in Flexor digitorum brevis fibers showed reduced MgATP-sensitivity in SUR2^wt/AV, dramatically so in SUR2^AV/AV mice; IC₅₀ for MgATP inhibition of KATP currents were 1.9 ± 0.5 × 10⁻⁵ M in SUR2^wt/AV and 8.6 ± 0.4 × 10⁻⁶ M in WT mice and was not measurable in SUR2^AV/AV. A slight rightward shift of sensitivity to inhibition by glibenclamide was detected in SUR2^AV/AV mice. Histopathological and qPCR analysis revealed atrophy of soleus and tibialis anterior muscles and up-regulation of atrogin-1 and MuRF1 mRNA in CS mice. (4) Conclusions: SUR2[A478V] “knock-in” mutation in mice impairs KATP channel modulation by MgATP, markedly so in SUR2^AV/AV, with atrophy and non-inflammatory edema in different skeletal muscle phenotypes.

Keywords: ATP-sensitive potassium channel; Cantu syndrome; glibenclamide; histopathology; patch-clamp; rare disease; skeletal muscle

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MDPI and ACS Style

Scala, R.; Maqoud, F.; Zizzo, N.; Passantino, G.; Mele, A.; Camerino, G.M.; McClenaghan, C.; Harter, T.M.; Nichols, C.G.; Tricarico, D. Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome. Cells 2021, 10, 1791. https://doi.org/10.3390/cells10071791

AMA Style

Scala R, Maqoud F, Zizzo N, Passantino G, Mele A, Camerino GM, McClenaghan C, Harter TM, Nichols CG, Tricarico D. Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome. Cells. 2021; 10(7):1791. https://doi.org/10.3390/cells10071791

Chicago/Turabian Style

Scala, Rosa, Fatima Maqoud, Nicola Zizzo, Giuseppe Passantino, Antonietta Mele, Giulia Maria Camerino, Conor McClenaghan, Theresa M. Harter, Colin G. Nichols, and Domenico Tricarico. 2021. "Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome" Cells 10, no. 7: 1791. https://doi.org/10.3390/cells10071791

APA Style

Scala, R., Maqoud, F., Zizzo, N., Passantino, G., Mele, A., Camerino, G. M., McClenaghan, C., Harter, T. M., Nichols, C. G., & Tricarico, D. (2021). Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome. Cells, 10(7), 1791. https://doi.org/10.3390/cells10071791

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Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome

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