Acute and chronic tirasemtiv treatment improves in vivo and in vitro muscle performance in actin-based nemaline myopathy mice

Winter, Josine M. de; Gineste, Charlotte; Minardi, Elisa; Brocca, Lorenza; Rossi, Maira; Borsboom, Tamara C.; Beggs, Alan H.; Bernard, Monique; Bendahan, David; Hwee, Darren T.; Malik, Fady I.; Pellegrino, Maria Antonietta; Bottinelli, Roberto; Gondin, Julien; Ottenheijm, Coen A.C.

doi:10.1093/hmg/ddab112

Cited by 14 publications

(6 citation statements)

References 57 publications

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“…It is known that tirasemtiv (Tir) binds specifically with high affinity to TN but does not interact with actin, myosin, or Tpm [ 55 ], so it can be used as a specific activator of calcium activation in skinned skeletal muscle fibers [ 56 , 57 , 58 ]. In addition, it was previously shown that the troponin activator CK-2066260, a structural analog of tirasemtiv, can correct the low calcium sensitivity of sarcomeres induced by the point mutation [ 59 ].…”

Section: Resultsmentioning

confidence: 99%

Molecular Mechanisms of Deregulation of Muscle Contractility Caused by the R168H Mutation in TPM3 and Its Attenuation by Therapeutic Agents

Karpicheva

Avrova

Bogdanov

et al. 2023

IJMS

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The substitution for Arg168His (R168H) in γ-tropomyosin (TPM3 gene, Tpm3.12 isoform) is associated with congenital muscle fiber type disproportion (CFTD) and muscle weakness. It is still unclear what molecular mechanisms underlie the muscle dysfunction seen in CFTD. The aim of this work was to study the effect of the R168H mutation in Tpm3.12 on the critical conformational changes that myosin, actin, troponin, and tropomyosin undergo during the ATPase cycle. We used polarized fluorescence microscopy and ghost muscle fibers containing regulated thin filaments and myosin heads (myosin subfragment-1) modified with the 1,5-IAEDANS fluorescent probe. Analysis of the data obtained revealed that a sequential interdependent conformational-functional rearrangement of tropomyosin, actin and myosin heads takes place when modeling the ATPase cycle in the presence of wild-type tropomyosin. A multistep shift of the tropomyosin strands from the outer to the inner domain of actin occurs during the transition from weak to strong binding of myosin to actin. Each tropomyosin position determines the corresponding balance between switched-on and switched-off actin monomers and between the strongly and weakly bound myosin heads. At low Ca2+, the R168H mutation was shown to switch some extra actin monomers on and increase the persistence length of tropomyosin, demonstrating the freezing of the R168HTpm strands close to the open position and disruption of the regulatory function of troponin. Instead of reducing the formation of strong bonds between myosin heads and F-actin, troponin activated it. However, at high Ca2+, troponin decreased the amount of strongly bound myosin heads instead of promoting their formation. Abnormally high sensitivity of thin filaments to Ca2+, inhibition of muscle fiber relaxation due to the appearance of the myosin heads strongly associated with F-actin, and distinct activation of the contractile system at submaximal concentrations of Ca2+ can lead to muscle inefficiency and weakness. Modulators of troponin (tirasemtiv and epigallocatechin-3-gallate) and myosin (omecamtiv mecarbil and 2,3-butanedione monoxime) have been shown to more or less attenuate the negative effects of the tropomyosin R168H mutant. Tirasemtiv and epigallocatechin-3-gallate may be used to prevent muscle dysfunction.

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Section: Resultsmentioning

confidence: 99%

Molecular Mechanisms of Deregulation of Muscle Contractility Caused by the R168H Mutation in TPM3 and Its Attenuation by Therapeutic Agents

Karpicheva

Avrova

Bogdanov

et al. 2023

IJMS

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“…NM is characterized by muscle weakness and diminished muscle size due to muscle atrophy. Both of these characteristics have also been observed in animal models with mutations in NEB or ACTA1 (encodes skeletal muscle α-actin) [ 22 , 23 , 34 , 35 , 36 ]. The molecular mechanism underlying the muscle weakness is likely to include alterations in the contraction mechanism due to mutations in the sarcomeric proteins that disrupt the normal cross-bridge behavior [ 6 , 37 , 38 , 39 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits

Lindqvist

Kolb

Winter

et al. 2022

IJMS

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Nemaline myopathy (NM) is characterized by skeletal muscle weakness and atrophy. No curative treatments exist for this debilitating disease. NM is caused by mutations in proteins involved in thin-filament function, turnover, and maintenance. Mutations in nebulin, encoded by NEB, are the most common cause. Skeletal muscle atrophy is tightly linked to upregulation of MuRF1, an E3 ligase, that targets proteins for proteasome degradation. Here, we report a large increase in MuRF1 protein levels in both patients with nebulin-based NM, also named NEM2, and in mouse models of the disease. We hypothesized that knocking out MuRF1 in animal models of NM with muscle atrophy would ameliorate the muscle deficits. To test this, we crossed MuRF1 KO mice with two NEM2 mouse models, one with the typical form and the other with the severe form. The crosses were viable, and muscles were studied in mice at 3 months of life. Ultrastructural examination of gastrocnemius muscle lacking MuRF1 and with severe NM revealed a small increase in vacuoles, but no significant change in the myofibrillar fractional area. MuRF1 deficiency led to increased weights of various muscle types in the NM models. However, this increase in muscle size was not associated with increased in vivo or in vitro force production. We conclude that knocking out MuRF1 in NEM2 mice increases muscle size, but does not improve muscle function.

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“…Например, тирасемтив, быстрый активатор скелетного тропонина, действующий на тонкие нити, продемонстрировал свою эффективность в качестве средства, которое увеличивает мышечную силу и может быть применено для компенсации гипотонии при мышечной дисфункции. В исследованиях на генетически-модифицированных мышах и клетках пациента с немалиновой миопатией, несущих мутацию актина (ACTA1H40Y), лечение тирасемтивом увеличивало инотропные показатели до показателей сравнимых со здоровым контролем [118].…”

Section: средства с положительным влиянием на мышечную силуunclassified

Conventional Approaches to the Therapy of Hereditary Myopathies

Pokrovskiy

Корокин

Krayushkina

et al. 2022

Farm. farmakol. (Pâtigorsk)

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The aim of the work was to analyze the available therapeutic options for the conventional therapy of hereditary myopathies.Materials and methods. When searching for the material for writing a review article, such abstract databases as PubMed and Google Scholar were used. The search was carried out on the publications during the period from 1980 to September 2022. The following words and their combinations were selected as parameters for the literature selection: “myopathy”, “Duchenne”, “myodystrophy”, “metabolic”, “mitochondrial”, “congenital”, “symptoms”, “replacement”, “recombinant”, “corticosteroids”, “vitamins”, “tirasemtiv”, “therapy”, “treatment”, “evidence”, “clinical trials”, “patients”, “dichloracetate”.Results. Congenital myopathies are a heterogeneous group of pathologies that are caused by atrophy and degeneration of muscle fibers due to mutations in genes. Based on a number of clinical and pathogenetic features, hereditary myopathies are divided into: 1) congenital myopathies; 2) muscular dystrophy; 3) mitochondrial and 4) metabolic myopathies. At the same time, treatment approaches vary significantly depending on the type of myopathy and can be based on 1) substitution of the mutant protein; 2) an increase in its expression; 3) stimulation of the internal compensatory pathways expression; 4) restoration of the compounds balance associated with the mutant protein function (for enzymes); 5) impact on the mitochondrial function (with metabolic and mitochondrial myopathies); 6) reduction of inflammation and fibrosis (with muscular dystrophies); as well as 7) an increase in muscle mass and strength. The current review presents current data on each of the listed approaches, as well as specific pharmacological agents with a description of their action mechanisms.Conclusion. Currently, the following pharmacological groups are used or undergoing clinical trials for the treatment of various myopathies types: inotropic, anti-inflammatory and antifibrotic drugs, antimyostatin therapy and the drugs that promote translation through stop codons (applicable for nonsense mutations). In addition, metabolic drugs, metabolic enzyme cofactors, mitochondrial biogenesis stimulators, and antioxidants can be used to treat myopathies. Finally, the recombinant drugs alglucosidase and avalglucosidase have been clinically approved for the replacement therapy of metabolic myopathies (Pompe’s disease).

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Acute and chronic tirasemtiv treatment improves in vivo and in vitro muscle performance in actin-based nemaline myopathy mice

Cited by 14 publications

References 57 publications

Molecular Mechanisms of Deregulation of Muscle Contractility Caused by the R168H Mutation in TPM3 and Its Attenuation by Therapeutic Agents

Molecular Mechanisms of Deregulation of Muscle Contractility Caused by the R168H Mutation in TPM3 and Its Attenuation by Therapeutic Agents

Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits

Conventional Approaches to the Therapy of Hereditary Myopathies

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