KBTBD13 is an actin-binding protein that modulates muscle kinetics

Winter, Josine M. de; Molenaar, J.; Yuen, Michaela; Pijl, Robbert van der; Shen, Shengyi; Conijn, Stefan; Locht, Martijn van de; Willigenburg, M. van; Bogaards, Sylvia J. P.; Kleef, Esmee S.B. van; Lassche, Saskia; Persson, Malin; Rassier, Dilson E.; Sztal, Tamar E.; Ruparelia, Avnika A.; Oorschot, Viola; Ramm, Georg; Hall, Thomas; Xiong, Zherui; Johnson, Christopher N.; Li, Frank; Kiss, Balázs; Lozano-Vidal, Noelia; Boon, Reinier A.; Marabita, Manuela; Nogara, Leonardo; Blaauw, Bert; Rodenburg, Richard J.; Küsters, Benno; Doorduin, Jonne; Beggs, Alan H.; Granzier, Henk; Campbell, Ken; Ma, Weikang; Irving, Thomas C.; Malfatti, Edoardo; Romero, Norma B.; Bryson-Richardson, Robert J.; Engelen, B.G.M. van; Voermans, Nicol C.; Ottenheijm, Coen A.C.

doi:10.1172/jci124000

Cited by 29 publications

(33 citation statements)

References 39 publications

(33 reference statements)

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“…A third KLHL family gene associated with autosomal nemaline myopathy is linked to dominant mutations in KBTBD13 [ 35 ]. Unlike the previously described genes, KBTBD13 is very small (3.1 kb) with no introns ( Supplemental Figure S6 ) and is expressed only at a low levels in SkM (TPM, 1.4) although the expression ratio in SkM to the median of non-SkM tissues is 25 ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

Ehrlich

Baribault

Ehrlich

2020

IJMS

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KLHL and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in cell function and disease (especially, KLHL40, KLHL41, KBTBD13, KEAP1, and ENC1), previous studies of epigenetic factors that affect transcription were predominantly limited to promoter DNA methylation. Using diverse tissue and cell culture whole-genome profiles, we examined 17 KLHL or KBTBD genes preferentially expressed in skeletal muscle or brain to identify tissue-specific enhancer and promoter chromatin, open chromatin (DNaseI hypersensitivity), and DNA hypomethylation. Sixteen of the 17 genes displayed muscle- or brain-specific enhancer chromatin in their gene bodies, and most exhibited specific intergenic enhancer chromatin as well. Seven genes were embedded in super-enhancers (particularly strong, tissue-specific clusters of enhancers). The enhancer chromatin regions typically displayed foci of DNA hypomethylation at peaks of open chromatin. In addition, we found evidence for an intragenic enhancer in one gene upregulating expression of its neighboring gene, specifically for KLHL40/HHATL and KLHL38/FBXO32 gene pairs. Many KLHL/KBTBD genes had tissue-specific promoter chromatin at their 5′ ends, but surprisingly, two (KBTBD11 and KLHL31) had constitutively unmethylated promoter chromatin in their 3′ exons that overlaps a retrotransposed KLHL gene. Our findings demonstrate the importance of expanding epigenetic analyses beyond the 5′ ends of genes in studies of normal and abnormal gene regulation.

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Section: Resultsmentioning

confidence: 99%

Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

Ehrlich

Baribault

Ehrlich

2020

IJMS

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“…In vitro characterization of intact muscle was performed as described previously ( 20 , 49 ). The experimental protocols consisted of a full tetanus at 150 Hz and a force-frequency protocol.…”

Section: Methodsmentioning

confidence: 99%

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

Winter

Gineste

Minardi

et al. 2021

Human Molecular Genetics

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Nemaline myopathy, a disease of the actin-based thin filament, is one of the most frequent congenital myopathies. To date, no specific therapy is available to treat muscle weakness in nemaline myopathy. We tested the ability of tirasemtiv, a fast skeletal troponin activator that targets the thin filament, to augment muscle force—both in vivo and in vitro—in a nemaline myopathy mouse model with a mutation (H40Y) in Acta1. In Acta1H40Y mice, treatment with tirasemtiv increased the force response of muscles to submaximal stimulation frequencies. This resulted in a reduced energetic cost of force generation, which increases the force production during a fatigue protocol. The inotropic effects of tirasemtiv were present in locomotor muscles and, albeit to a lesser extent, in respiratory muscles, and they persisted during chronic treatment, an important finding as respiratory failure is the main cause of death in patients with congenital myopathy. Finally, translational studies on permeabilized muscle fibers isolated from a biopsy of a patient with the ACTA1H40Y mutation revealed that at physiological Ca2+ concentrations, tirasemtiv increased force generation to values that were close to those generated in muscle fibers of healthy subjects. These findings indicate the therapeutic potential of fast skeletal muscle troponin activators to improve muscle function in nemaline myopathy due to the ACTA1H40Y mutation, and future studies should assess their merit for other forms of nemaline myopathy and for other congenital myopathies.

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“…Transcranial magnetic stimulation (TMS) of the motor cortex can induce muscle relaxation by abruptly inhibiting corticospinal drive. Thus, the maximal rate of muscle relaxation can be assessed to detect delayed muscle relaxation, which is experienced as muscle slowness in NEM6 patients [22] . Next, she discussed results of some of the studies on experienced fatigue in adults with various neuromuscular disorders.…”

Section: Clinical Outcome Measuresmentioning

confidence: 99%