Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing

Will, Rainer; Eden, Matthias; Just, Steffen; Hansen, Arne; Eder, Alexandra; Frank, Derk; Kühn, Christian; Seeger, Thalia S.; Oehl, Ulrike; Wiemann, Stefan; Korn, Bernhard; Koegl, Manfred; Rottbauer, Wolfgang; Eschenhagen, Thomas; Katus, Hugo A.; Frey, Norbert

doi:10.1161/circresaha.110.222372

Cited by 49 publications

(37 citation statements)

References 53 publications

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“…Leucine-rich repeat-containing protein 39 (LRRC39), myomesin 1 (MYOM1), and 2 (MYOM2), components of M-bands, 18 increased at 360-day differentiation compared with 30-day differentiation, supporting the observation of M-band formation in 360-day hiPSC-CMs (Figure 8). However, the expression levels of the M-band-specific proteins in the hiPSC-CMs were lower compared with those of the adult heart.…”

Section: Expression Of Cardiac-specific Genessupporting

confidence: 73%

Ultrastructural Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Long-Term Culture

Kamakura

Makiyama

Sasaki

et al. 2013

Circ J

264

224

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Background:In the short-to mid-term, cardiomyocytes generated from human-induced pluripotent stem cells (hiPSC-CMs) have been reported to be less mature than those of adult hearts. However, the maturation process in a long-term culture remains unknown. Methods and Results:A hiPSC clone generated from a healthy control was differentiated into CMs through embryoid body (EB) formation. The ultrastructural characteristics and gene expressions of spontaneously contracting EBs were analyzed through 1-year of culture after cardiac differentiation was initiated. The 14-day-old EBs contained a low number of myofibrils, which lacked alignment, and immature high-density Z-bands lacking A-, H-, I-, and Mbands. Through the long-term culture up to 180 days, the myofibrils became more tightly packed and formed parallel arrays accompanied by the appearance of mature Z-, A-, H-, and I-bands, but not M-bands. Notably, M-bands were finally detected in 360-day-old EBs. The expression levels of the M-band-specific genes in hiPSC-CMs remained lower in comparison with those in the adult heart. Immunocytochemistry indicated increasing number of MLC2v-positive/MLC2a-negative cells with decreasing number of MLC2v/MLC2a double-positive cells, indicating maturing of ventricular-type CMs. Conclusions:The structural maturation process of hiPSC-CMs through 1-year of culture revealed ultrastructural sarcomeric changes accompanied by delayed formation of M-bands. Our study provides new insight into the maturation process of hiPSC-CMs. (Circ J 2013; 77: 1307 -1314

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Section: Expression Of Cardiac-specific Genessupporting

confidence: 73%

Ultrastructural Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Long-Term Culture

Kamakura

Makiyama

Sasaki

et al. 2013

Circ J

264

224

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“…On the basis of the notion that proteins specifically expressed in the heart are likely to play a role in cardiac pathophysiology23, we systematically screened the expressed sequence tag (EST) databases for sequences predominantly found in cardiac complementary DNA (cDNA) libraries24. Data extraction relied on the T-STAG (Tissue-Specific Transcripts and Genes; http://tstag.molgen.mpg.de/) and the Unigene (National Center for Biotechnology; http://www.ncbi.nlm.nih.gov/unigene) databases.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, improved understanding of the molecular mechanisms underlying heart failure is still urgently needed to develop novel targeted treatment strategies. Thus, to search for new molecular targets affecting cardiac function, we took an in silico approach to identify novel genes mainly expressed in cardiac tissues24. mRNA and protein expression analyses confirmed an enrichment of Myoscape in human and murine cardiac tissue.…”

Section: Discussionmentioning

confidence: 99%

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

et al. 2016

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Calcium signalling plays a critical role in the pathogenesis of heart failure. Here we describe a cardiac protein named Myoscape/FAM40B/STRIP2, which directly interacts with the L-type calcium channel. Knockdown of Myoscape in cardiomyocytes decreases calcium transients associated with smaller Ca2+ amplitudes and a lower diastolic Ca2+ content. Likewise, L-type calcium channel currents are significantly diminished on Myoscape ablation, and downregulation of Myoscape significantly reduces contractility of cardiomyocytes. Conversely, overexpression of Myoscape increases global Ca2+ transients and enhances L-type Ca2+ channel currents, and is sufficient to restore decreased currents in failing cardiomyocytes. In vivo, both Myoscape-depleted morphant zebrafish and Myoscape knockout (KO) mice display impairment of cardiac function progressing to advanced heart failure. Mechanistically, Myoscape-deficient mice show reduced L-type Ca2+currents, cell capacity and calcium current densities as a result of diminished LTCC surface expression. Finally, Myoscape expression is reduced in hearts from patients suffering of terminal heart failure, implying a role in human disease.

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“…acts as a mechanosensor at the cardiomyocyte M-line by regulating serum response factor-dependent transcription (51).…”

Section: Discussionmentioning

confidence: 99%

LRRC10 is required to maintain cardiac function in response to pressure overload

Brody

Feng

Grimes

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Brody MJ, Feng L, Grimes AC, Hacker TA, Olson TM, Kamp TJ, Balijepalli RC, Lee Y. LRRC10 is required to maintain cardiac function in response to pressure overload. Am J Physiol Heart Circ Physiol 310: H269 -H278, 2016. First published November 25, 2015 doi:10.1152/ajpheart.00717.2014.-We previously reported that the cardiomyocyte-specific leucine-rich repeat containing protein (LRRC)10 has critical functions in the mammalian heart. In the present study, we tested the role of LRRC10 in the response of the heart to biomechanical stress by performing transverse aortic constriction on Lrrc10-null (Lrrc10 Ϫ/Ϫ ) mice. Mild pressure overload induced severe cardiac dysfunction and ventricular dilation in Lrrc10 Ϫ/Ϫ mice compared with control mice. In addition to dilation and cardiomyopathy, Lrrc10 Ϫ/Ϫ mice showed a pronounced increase in heart weight with pressure overload stimulation and a more dramatic loss of cardiac ventricular performance, collectively suggesting that the absence of LRRC10 renders the heart more disease prone with greater hypertrophy and structural remodeling, although rates of cardiac fibrosis and myocyte dropout were not different from control mice. Lrrc10 Ϫ/Ϫ cardiomyocytes also exhibited reduced contractility in response to ␤-adrenergic stimulation, consistent with loss of cardiac ventricular performance after pressure overload. We have previously shown that LRRC10 interacts with actin in the heart. Here, we show that His 150 of LRRC10 was required for an interaction with actin, and this interaction was reduced after pressure overload, suggesting an integral role for LRRC10 in the response of the heart to mechanical stress. Importantly, these experiments demonstrated that LRRC10 is required to maintain cardiac performance in response to pressure overload and suggest that dysregulated expression or mutation of LRRC10 may greatly sensitize human patients to more severe cardiac disease in conditions such as chronic hypertension or aortic stenosis. CARDIOMYOCYTE HYPERTROPHY in response to extracellular stimuli, such as neurohumoral or growth factor stimulation of membrane-bound receptors (13, 23, 44), or in response to mechanical stretch or strain that is sensed by mechanosensory machinery embedded in the Z-disc cytoskeleton, and sarcolemma (25, 38, 49). At the whole organ level, the heart undergoes hypertrophy as an adaptive mechanism to maintain cardiac output and reduce ventricular wall stress (20,23,38). While initially beneficial, prolonged cardiac hypertrophy becomes maladaptive and progresses to cardiac dilation, decompensation, heart failure, and/or sudden death (20,23,38). Cardiac hypertrophy can be induced by a number of cardiovascular diseases, such as myocardial infarction or chronic hypertension (23, 37). Indeed, high blood pressure is a common precursor to heart disease, particularly in the United States, where chronic hypertension is widespread (18,21,42). Despite increased awareness and treatment of hypertension, recent epidemiological studies have suggested that its prevalence con...

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Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing

Cited by 49 publications

References 53 publications

Ultrastructural Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Long-Term Culture

Ultrastructural Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Long-Term Culture

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

LRRC10 is required to maintain cardiac function in response to pressure overload

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