TY - JOUR

T1 - Molecular Mechanisms of Muscle Weakness Associated with E173A Mutation in Tpm3.12. Troponin Ca2+ Sensitivity Inhibitor W7 Can Reduce the Damaging Effect of This Mutation

AU - Borovikov, Yurii S.

AU - Simonyan, Armen O.

AU - Avrova, Stanislava V.

AU - Sirenko, Vladimir V.

AU - Redwood, Charles S.

AU - Karpicheva, Olga E.

N1 - Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/6/22

Y1 - 2020/6/22

N2 - Substitution of Ala for Glu residue in position 173 of γ-tropomyosin (Tpm3.12) is associatedwith muscle weakness. Here we observe that this mutation increases myofilament Ca2+-sensitivityand inhibits in vitro actin-activated ATPase activity of myosin subfragment-1 at high Ca2+. In orderto determine the critical conformational changes in myosin, actin and tropomyosin caused by themutation, we used the technique of polarized fluorimetry. It was found that this mutation changesthe spatial arrangement of actin monomers and myosin heads, and the position of the mutanttropomyosin on the thin filaments in muscle fibres at various mimicked stages of the ATPase cycle.At low Ca2+ the E173A mutant tropomyosin shifts towards the inner domains of actin at all stages ofthe cycle, and this is accompanied by an increase in the number of switched-on actin monomers andmyosin heads strongly bound to F-actin even at relaxation. Contrarily, at high Ca2+ the amount of thestrongly bound myosin heads slightly decreases. These changes in the balance of the strongly boundmyosin heads in the ATPase cycle may underlie the occurrence of muscle weakness. W7, an inhibitorof troponin Ca2+-sensitivity, restores the increase in the number of myosin heads strongly bound toF-actin at high Ca2+ and stops their strong binding at relaxation, suggesting the possibility of usingCa2+-desensitizers to reduce the damaging effect of the E173A mutation on muscle fibre contractility.

AB - Substitution of Ala for Glu residue in position 173 of γ-tropomyosin (Tpm3.12) is associatedwith muscle weakness. Here we observe that this mutation increases myofilament Ca2+-sensitivityand inhibits in vitro actin-activated ATPase activity of myosin subfragment-1 at high Ca2+. In orderto determine the critical conformational changes in myosin, actin and tropomyosin caused by themutation, we used the technique of polarized fluorimetry. It was found that this mutation changesthe spatial arrangement of actin monomers and myosin heads, and the position of the mutanttropomyosin on the thin filaments in muscle fibres at various mimicked stages of the ATPase cycle.At low Ca2+ the E173A mutant tropomyosin shifts towards the inner domains of actin at all stages ofthe cycle, and this is accompanied by an increase in the number of switched-on actin monomers andmyosin heads strongly bound to F-actin even at relaxation. Contrarily, at high Ca2+ the amount of thestrongly bound myosin heads slightly decreases. These changes in the balance of the strongly boundmyosin heads in the ATPase cycle may underlie the occurrence of muscle weakness. W7, an inhibitorof troponin Ca2+-sensitivity, restores the increase in the number of myosin heads strongly bound toF-actin at high Ca2+ and stops their strong binding at relaxation, suggesting the possibility of usingCa2+-desensitizers to reduce the damaging effect of the E173A mutation on muscle fibre contractility.

KW - TROPOMYOSIN

KW - mutations in tropomyosin

KW - muscle weakness

KW - congenital myopathy

KW - Ca2+-sensitivity of myofilament

KW - ATPase activity of myosin

KW - troponin inhibitor W7

KW - Tropomyosin

KW - Congenital myopathy

KW - Mutations in tropomyosin

KW - Troponin inhibitor W7

KW - Muscle weakness

KW - Ca -sensitivity of myofilament

UR - https://www.mdpi.com/1422-0067/21/12/4421

UR - http://www.scopus.com/inward/record.url?scp=85087098258&partnerID=8YFLogxK

U2 - 10.3390/ijms21124421

DO - 10.3390/ijms21124421

M3 - Article

VL - 21

SP - 1

EP - 17

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 12

M1 - 4421

ER -