X-ray recordings reveal how a human disease-linked skeletal muscle α-actin mutation leads to contractile dysfunction

Ochala, Julien; Ravenscroft, Gianina; McNamara, Elyshia; Nowak, Kristen J.; Iwamoto, Hiroyuki

doi:10.1016/j.jsb.2015.09.008

Cited by 9 publications

(8 citation statements)

References 25 publications

(37 reference statements)

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“…3C, P ¼ 0.0013). This is in accordance with our previously published data (32,33). Treatment with mRK35 significantly increased absolute force in treated mice of both genotypes (C57/VEH: 359.…”

Section: Physiological Studiessupporting

confidence: 93%

Myostatin inhibition using mRK35 produces skeletal muscle growth and tubular aggregate formation in wild type and TgACTA1D286G nemaline myopathy mice

Tinklenberg

Siebers

Beatka

et al. 2017

Human Molecular Genetics

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Nemaline myopathy (NM) is a heterogeneous congenital skeletal muscle disease with cytoplasmic rod-like structures (nemaline bodies) in muscle tissue. While weakness in NM is related to contractile abnormalities, myofiber smallness is an additional abnormality in NM that may be treatable. We evaluated the effects of mRK35 (a myostatin inhibitor developed by Pfizer) treatment in the TgACTA1D286G mouse model of NM. mRK35 induced skeletal muscle growth that led to significant increases in animal bodyweight, forelimb grip strength and muscle fiber force, although it should be noted that animal weight and forelimb grip strength in untreated TgACTA1D286G mice was not different from controls. Treatment was also associated with an increase in the number of tubular aggregates found in skeletal muscle. These findings suggest that myostatin inhibition may be useful in promoting muscle growth and strength in Acta1-mutant muscle, while also further establishing the relationship between low levels of myostatin and tubular aggregate formation.

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Section: Physiological Studiessupporting

confidence: 93%

Myostatin inhibition using mRK35 produces skeletal muscle growth and tubular aggregate formation in wild type and TgACTA1D286G nemaline myopathy mice

Tinklenberg

Siebers

Beatka

et al. 2017

Human Molecular Genetics

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“…The arrays were then transferred to the skinning solution and stored at -20°C. Approximately 80 arrays were mounted (10 arrays per mouse – four knock-in and four wild-type mice – corresponding to approximately 2,400 attached fibers) (Ochala et al, 2015; Chan et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

“…Actin monomers of the thin filaments directly interact with myosin molecules to form cross-bridges that initiate force development and motion at the sarcomere and myofiber levels (Gordon et al, 2000). Missense ACTA1 mutations, and thus, single amino acid replacements in actin proteins, are now known to depress myosin cross-bridge formation and myofiber force production explaining in part why patients experience muscle weakness and have myopathic phenotypes (Lindqvist et al, 2012, 2013, 2016; Ochala et al, 2012, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…We focused our attention on D286G which is located in subdomain 3 at the actin-actin interface (Ravenscroft et al, 2011a). Even though D286G does not have any known interaction with myosin, tropomyosin and/or troponin molecules, it has been linked to improper myosin binding (Ochala et al, 2012, 2015) and nemaline myopathy in mice and humans (Ravenscroft et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Consequences of the Myopathy-Related D286G Mutation on Actin Function

et al. 2018

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Myopathies are notably associated with mutations in genes encoding proteins known to be essential for the force production of skeletal muscle fibers, such as skeletal alpha-actin. The exact molecular mechanisms by which these specific defects induce myopathic phenotypes remain unclear. Hence, in the present study, to better understand actin dysfunction, we conducted a molecular dynamic simulation together with ex vivo experiments of the specific muscle disease-causing actin mutation, D286G located in the actin-actin interface. Our computational study showed that D286G impairs the flexural rigidity of actin filaments. However, upon activation, D286G did not have any direct consequences on actin filament extension. Hence, D286G may alter the structure of actin filaments but, when expressed together with normal actin molecules, it may only have minor effects on the ex vivo mechanics of actin filaments upon skeletal muscle fiber contraction.

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“…From these findings, they concluded that a smaller shift of mutant tropomyosin in patient skeletal muscle fibers limited the contractile interaction between myosin heads and actin so as to decrease the contractile force. Ochala's group also studied the structural basis of myopathy caused by the D286G mutation of actin using a transgenic mouse 41) . In skinned skeletal muscle fibers from the transgenic mouse, a decrease in 1/14.3 nm -1 myosin meridional reflection ity via a modified interaction with the troponin I-subunit, while E244D causes hypercontractility by affecting the interaction between the T-subunit and tropomyosin and/or actin independently of interaction with the I-subunit.…”

Section: Attempts To Reveal Pathogenesis Of Familial Diseasesmentioning

confidence: 99%

Approaches to physical fitness and sports medicine through X-ray diffraction analysis of striated muscle

Yamaguchi

Takemori

Kimura

et al. 2016

JPFSM

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X-ray diffraction analysis is a method to obtain information about periodically repeated structures. When striated muscle is irradiated with X-ray, many of the reflections and the layer lines, which convey information about molecular structures within the muscle fiber, are obtained without chemical modification. Two of the strong equatorial reflections, 1,0 reflection arising from a thick filament array and 1,1 reflection arising from a thick and thin filament array appear on the equator giving information about distance and mass distribution on a radial plane. Thus a 1,1/1,0 intensity ratio is a good index of radial distribution of myosin heads. Meridional reflections and layer lines, such as a myosin reflection of the 14.3 nm repeat and myosin or actin layer lines, give information about longitudinal arrangement of the molecules. Since they are affected by the movement of the myosin heads and the shifting motion of troponin-tropomyosin on the actin filament, they can be used to detect conformational changes of contractile and regulatory systems upon muscle activation. The X-ray diffraction method has been applied to yield fruitful results for many problems such as muscle atrophy by disuse, functional modulation by myosin regulatory light chain phosphorylation, differential characteristics of slow and fast skeletal muscle structure, and pathogenesis of some types of the familial myopathy. The approach using X-ray diffraction analysis will continuously serve as a potent tool for resolving problems in the field of physical fitness and sports medicine.

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X-ray recordings reveal how a human disease-linked skeletal muscle α-actin mutation leads to contractile dysfunction

Cited by 9 publications

References 25 publications

Myostatin inhibition using mRK35 produces skeletal muscle growth and tubular aggregate formation in wild type and TgACTA1D286G nemaline myopathy mice

Myostatin inhibition using mRK35 produces skeletal muscle growth and tubular aggregate formation in wild type and TgACTA1D286G nemaline myopathy mice

Molecular Consequences of the Myopathy-Related D286G Mutation on Actin Function

Approaches to physical fitness and sports medicine through X-ray diffraction analysis of striated muscle

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