TY - JOUR

T1 - Molecular Mechanisms of the Deregulation of Muscle Contraction Induced by the R90P Mutation in Tpm3.12 and the Weakening of This Effect by BDM and W7

AU - Borovikov, Y.S.

AU - Andreeva, Daria D

AU - Avrova, S.V.

AU - Sirenko, V.V.

AU - Simonyan, Armen O.

AU - Redwood, C.S.

AU - Karpicheva, O.E.

N1 - Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/6/2

Y1 - 2021/6/2

N2 - Point mutations in the genes encoding the skeletal muscle isoforms of tropomyosin cancause a range of muscle diseases. The amino acid substitution of Arg for Pro residue in the 90th position (R90P) in γ-tropomyosin (Tpm3.12) is associated with congenital fiber type disproportionand muscle weakness. The molecular mechanisms underlying muscle dysfunction in this diseaseremain unclear. Here, we observed that this mutation causes an abnormally high Ca2+-sensitivity ofmyofilaments in vitro and in muscle fibers. To determine the critical conformational changes thatmyosin, actin, and tropomyosin undergo during the ATPase cycle and the alterations in these changescaused by R90P replacement in Tpm3.12, we used polarized fluorimetry. It was shown that the R90Pmutation inhibits the ability of tropomyosin to shift towards the outer domains of actin, which isaccompanied by the almost complete depression of troponin’s ability to switch actin monomers offand to reduce the amount of the myosin heads weakly bound to F-actin at a low Ca2+. These changesin the behavior of tropomyosin and the troponin–tropomyosin complex, as well as in the balance ofstrongly and weakly bound myosin heads in the ATPase cycle may underlie the occurrence of bothabnormally high Ca2+-sensitivity and muscle weakness. BDM, an inhibitor of myosin ATPase activity,and W7, a troponin C antagonist, restore the ability of tropomyosin for Ca2+-dependent movementand the ability of the troponin–tropomyosin complex to switch actin monomers off, demonstrating aweakening of the damaging effect of the R90P mutation on muscle contractility.

AB - Point mutations in the genes encoding the skeletal muscle isoforms of tropomyosin cancause a range of muscle diseases. The amino acid substitution of Arg for Pro residue in the 90th position (R90P) in γ-tropomyosin (Tpm3.12) is associated with congenital fiber type disproportionand muscle weakness. The molecular mechanisms underlying muscle dysfunction in this diseaseremain unclear. Here, we observed that this mutation causes an abnormally high Ca2+-sensitivity ofmyofilaments in vitro and in muscle fibers. To determine the critical conformational changes thatmyosin, actin, and tropomyosin undergo during the ATPase cycle and the alterations in these changescaused by R90P replacement in Tpm3.12, we used polarized fluorimetry. It was shown that the R90Pmutation inhibits the ability of tropomyosin to shift towards the outer domains of actin, which isaccompanied by the almost complete depression of troponin’s ability to switch actin monomers offand to reduce the amount of the myosin heads weakly bound to F-actin at a low Ca2+. These changesin the behavior of tropomyosin and the troponin–tropomyosin complex, as well as in the balance ofstrongly and weakly bound myosin heads in the ATPase cycle may underlie the occurrence of bothabnormally high Ca2+-sensitivity and muscle weakness. BDM, an inhibitor of myosin ATPase activity,and W7, a troponin C antagonist, restore the ability of tropomyosin for Ca2+-dependent movementand the ability of the troponin–tropomyosin complex to switch actin monomers off, demonstrating aweakening of the damaging effect of the R90P mutation on muscle contractility.

KW - tropomyosin

KW - mutations in tropomyosin

KW - muscle weakness

KW - congenital myopathy

KW - Ca2+ - sensitivity of myofilament

KW - ATPase activity of myosin

KW - 2,3-butanedione monoxime (BDM)

KW - n-(6- aminohexyl) 5-chloro-1-naphthalenesulfonamide (W7)

KW - N-(6-ami-nohexyl) 5-chloro-1-naphthalenesulfonamide (W7)

KW - Tropomyosin

KW - Congenital myopathy

KW - Mutations in tropomyosin

KW - Muscle weakness

KW - Ca -sensitivity of myofilament

UR - https://www.mdpi.com/1422-0067/22/12/6318

UR - http://www.scopus.com/inward/record.url?scp=85107726363&partnerID=8YFLogxK

U2 - 10.3390/ijms22126318

DO - 10.3390/ijms22126318

M3 - Article

VL - 22

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 12

M1 - 6318

ER -