STAC3-related myopathy: A Report of a Cohort of Seven Saudi Arabian Patients.

AIM: The study aims to review all the genetically confirmed STAC3-related myopathy being followed in a single center in the Eastern Province of Saudi Arabia. METHODOLOGY: A retrospective review of all genetically confirmed STAC3-related myopathy followed in our clinic has been conducted. RESULTS: 7 patients with STAC3-related myopathy have been found in our cohort, with all the patients presenting with infantile hypotonia, myopathic facies, and muscle weakness in the first year of life. Feeding difficulties and failure to thrive were found in all patients except one who died during the neonatal period. Respiratory muscle involvement was also found in 5 out of 6 formally tested patients while cleft palate was found in 5 patients. CONCLUSION: STAC3-related myopathy is a relatively rare, malignant hyperthermia (MH)--causing muscle disease described in specific, highly consanguineous populations. Making the diagnosis in myopathic patients with cleft palate preoperatively can prevent MH-induced, anesthesia-related perioperative complications.

Why Craniofacial Surgeons/Researchers Need to be Aware of Native American Myopathy?

Congenital myopathy type 13 (CMYO13), also known as Native American myopathy, is a rare muscle disease characterized by early-onset hypotonia, muscle weakness, delayed motor milestones, and susceptibility to malignant hyperthermia. The phenotypic spectrum of congenital myopathy type 13 is expanding, with milder forms reported in non-native American patients. The first description of the disease dates to 1987 when Bailey and Bloch described an infant belonging to a Native American tribe with cleft palate, micrognathia, arthrogryposis, and general-anesthesia-induced malignant hyperthermia reaction; the cause of the latter remains poorly defined in this rare disease. The pan-ethnic distribution, as well as its predisposition to malignant hyperthermia, makes the identification of CMYO13 essential to avoid life-threatening, anesthesia-related complications. In this article, we are going to review the clinical phenotype of this disease and the pathophysiology of this rare disease with a focus on two unique features of the disease, namely cleft palate and malignant hyperthermia. We also highlight the importance of recognizing this disease's expanding phenotypic spectrum-including its susceptibility to malignant hyperthermia-and providing appropriate care to affected individuals and families.

Caspase Cleavage of Gelsolin Is an Inductive Cue for Pathologic Cardiac Hypertrophy.

Background Cardiac hypertrophy is an adaptive remodeling event that may improve or diminish contractile performance of the heart. Physiologic and pathologic hypertrophy yield distinct outcomes, yet both are dependent on caspase-directed proteolysis. This suggests that each form of myocardial growth may derive from a specific caspase cleavage event(s). We examined whether caspase 3 cleavage of the actin capping/severing protein gelsolin is essential for the development of pathologic hypertrophy. Methods and Results Caspase targeting of gelsolin was established through protein analysis of hypertrophic cardiomyocytes and mass spectrometry mapping of cleavage sites. Pathologic agonists induced late-stage caspase-mediated cleavage of gelsolin. The requirement of caspase-mediated gelsolin cleavage for hypertrophy induction was evaluated in primary cardiomyocytes by cell size analysis, monitoring of prohypertrophy markers, and measurement of hypertrophy-related transcription activity. The in vivo impact of caspase-mediated cleavage was investigated by echo-guided intramyocardial injection of adenoviral-expressed gelsolin. Expression of the N-terminal gelsolin caspase cleavage fragment was necessary and sufficient to cause pathologic remodeling in isolated cardiomyocytes and the intact heart, whereas expression of a noncleavable form prevents cardiac remodeling. Alterations in myocardium structure and function were determined by echocardiography and end-stage cardiomyocyte cell size analysis. Gelsolin secretion was also monitored for its impact on naïve cells using competitive antibody trapping, demonstrating that hypertrophic agonist stimulation of cardiomyocytes leads to gelsolin secretion, which induces hypertrophy in naïve cells. Conclusions These results suggest that cell autonomous caspase cleavage of gelsolin is essential for pathologic hypertrophy and that cardiomyocyte secretion of gelsolin may accelerate this negative remodeling response.

Effects of exercise training and TrkB blockade on cardiac function and BDNF-TrkB signaling postmyocardial infarction in rats.

Exercise training is beneficial for preserving cardiac function postmyocardial infarction (post-MI), but the underlying mechanisms are not well understood. We investigated one possible mechanism, brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling, with the TrkB blocker ANA-12 (0.5 mg·kg-1·day-1). Male Wistar rats underwent sham surgery or ligation of the left descending coronary artery. The surviving MI rats were allocated as follows: sedentary MI rats treated with vehicle, exercise-trained MI rats treated with vehicle, and exercise-trained MI rats treated with ANA-12. Exercise training was done 5 days/wk for 4 wk on a motor-driven treadmill. At the end, left ventricular (LV) function was evaluated by echocardiography and a Millar catheter. Mature BDNF and downstream effectors of BDNF-TrkB signaling, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Akt, and AMP-activated protein kinase (AMPK), were assessed in the noninfarct area of the LV by Western blot analysis. Exercise training increased stroke volume and cardiac index and attenuated the decrease in ejection fraction (EF) and increase in LV end-diastolic pressure post-MI. ANA-12 blocked the improvement of EF and attenuated the increases in stroke volume and cardiac index but did not affect LV end-diastolic pressure. Exercise training post-MI prevented decreases in mature BDNF, phosphorylated (p-)CaMKII, p-Akt, and p-AMPKα expression. These effects were all blocked by ANA-12 except for p-AMPKα. In conclusion, the exercise-induced improvement of EF is mediated by the BDNF-TrkB axis and the downstream effectors CaMKII and Akt. BDNF-TrkB signaling appears to contribute to the improvement in systolic function by exercise training. NEW & NOTEWORTHY Exercise training improves ejection fraction and left ventricular end-diastolic pressure (LVEDP) and increases stroke volume and cardiac index in rats postmyocardial infarction (post-MI). The improvement of EF but not LVEDP is mediated by activation of the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) axis and downstream effectors Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Akt. This suggests that activation of BDNF-TrkB signaling and CaMKII and Akt is a promising target to attenuate progressive cardiac dysfunction post-MI.

Deletion of MLIP (muscle-enriched A-type lamin-interacting protein) leads to cardiac hyperactivation of Akt/mammalian target of rapamycin (mTOR) and impaired cardiac adaptation.

Aging and diseases generally result from tissue inability to maintain homeostasis through adaptation. The adult heart is particularly vulnerable to disequilibrium in homeostasis because its regenerative abilities are limited. Here, we report that MLIP (muscle enriched A-type lamin-interacting protein), a unique protein of unknown function, is required for proper cardiac adaptation. Mlip(-/-) mice exhibited normal cardiac function despite myocardial metabolic abnormalities and cardiac-specific overactivation of Akt/mTOR pathways. Cardiac-specific MLIP overexpression led to an inhibition of Akt/mTOR, providing evidence of a direct impact of MLIP on these key signaling pathways. Mlip(-/-) hearts showed an impaired capacity to adapt to stress (isoproterenol-induced hypertrophy), likely because of deregulated Akt/mTOR activity. Genome-wide association studies showed a genetic association between Mlip and early response to cardiac stress, supporting the role of MLIP in cardiac adaptation. Together, these results revealed that MLIP is required for normal myocardial adaptation to stress through integrated regulation of the Akt/mTOR pathways.

Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis.

Homozygous cardiac myosin binding protein C-deficient (Mybpc(t/t)) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpc(t/t) myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpc(t/t) myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpc(t/t) mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3(+/-) individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3(-/-) mice is primarily myocyte hyperplasia.

Identification of a novel muscle A-type lamin-interacting protein (MLIP).

Mutations in the A-type lamin (LMNA) gene are associated with age-associated degenerative disorders of mesenchymal tissues, such as dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and limb-girdle muscular dystrophy. The molecular mechanisms that connect mutations in LMNA with different human diseases are poorly understood. Here, we report the identification of a Muscle-enriched A-type Lamin-interacting Protein, MLIP (C6orf142 and 2310046A06rik), a unique single copy gene that is an innovation of amniotes (reptiles, birds, and mammals). MLIP encodes alternatively spliced variants (23-57 kDa) and possesses several novel structural motifs not found in other proteins. MLIP is expressed ubiquitously and most abundantly in heart, skeletal, and smooth muscle. MLIP interacts directly and co-localizes with lamin A and C in the nuclear envelope. MLIP also co-localizes with promyelocytic leukemia (PML) bodies within the nucleus. PML, like MLIP, is only found in amniotes, suggesting that a functional link between the nuclear envelope and PML bodies may exist through MLIP. Down-regulation of lamin A/C expression by shRNA results in the up-regulation and mislocalization of MLIP. Given that MLIP is expressed most highly in striated and smooth muscle, it is likely to contribute to the mesenchymal phenotypes of laminopathies.

IRF2BP2 is a skeletal and cardiac muscle-enriched ischemia-inducible activator of VEGFA expression.

We sought to identify an essential component of the TEAD4/VGLL4 transcription factor complex that controls vascular endothelial growth factor A (VEGFA) expression in muscle. A yeast 2-hybrid screen was used to clone a novel component of the TEAD4 complex from a human heart cDNA library. We identified interferon response factor 2 binding protein 2 (IRF2BP2) and confirmed its presence in the TEAD4/VGLL4 complex in vivo by coimmunoprecipitation and mammalian 2-hybrid assays. Coexpression of IRF2BP2 with TEAD4/VGLL4 or TEAD1 alone potently activated, whereas knockdown of IRF2BP2 reduced, VEGFA expression in C(2)C(12) muscle cells. Thus, IRF2BP2 is required to activate VEGFA expression. In mouse embryos, IRF2BP2 was ubiquitously expressed but became progressively enriched in the fetal heart, skeletal muscles, and lung. Northern blot analysis revealed high levels of IRF2BP2 mRNA in adult human heart and skeletal muscles, but immunoblot analysis showed low levels of IRF2BP2 protein in skeletal muscle, indicating post-transcriptional regulation of IRF2BP2 expression. IRF2BP2 protein levels are markedly increased by ischemia in skeletal and cardiac muscle compared to normoxic controls. IRF2BP2 is a novel ischemia-induced coactivator of VEGFA expression that may contribute to revascularization of ischemic cardiac and skeletal muscles.

Role of potassium channels in stretch-promoted atrial natriuretic factor secretion.

The cardiac polypeptide hormone atrial natriuretic factor (ANF) plays important roles in the regulation of blood volume and pressure. Few specific details are known about basal or stretch-promoted ANF secretion. Here, we investigated the involvement of K(+) channels in ANF secretion based on investigations of their nature as revealed by oligonucleotide microarray analysis and on protein-protein interactions evidenced by a yeast two-hybrid approach using a heterotrimeric Galphao-1 G protein subunit, which is particularly abundant in the atrium. Based on these data, we investigated the effect of drugs known to pharmacologically affect the function of specific K(+) channels on ANF secretion from the isolated rat atrium. These included adenosine triphosphate-sensitive K(+) channels, TWIK-related K(+) channel 1 (TREK-1), and the Ca(+2)-activated intermediate conductance K(+) channel (SK4). The sulfonylurea ligands tolbutamide and repaglinide, but not glibenclamide, increased stretch-promoted ANF secretion. The channel openers diazoxide, pinacidil, and cromakalim all decreased this type of stimulated ANF secretion. TRAM 34, a specific SK4 inhibitor, and oleylamine, a nonspecific TREK-1 inhibitor, significantly decreased or increased respectively, both basal and stretch-stimulated ANF secretion. Inhibition of Gi/o by pretreatment with Pertussis toxin often significantly affected the effect of these treatments. We concluded that the atria express K(+) channels that are related to Gi/o protein signaling and that significantly affect the endocrine function of the heart. These findings are significant for the development of therapeutic drugs with properties related to the manipulation of ANF plasma levels.

E2F3 plays an essential role in cardiac development and function.

The E2F transcription factors are key downstream targets of the retinoblastoma protein tumor suppressor. They are known to regulate the expression of genes that control fundamental biological processes including cellular proliferation, apoptosis and differentiation. However, considerable questions remain about the precise roles of the individual E2F family members. This study shows that E2F3 is essential for normal cardiac development. E2F3-loss impairs the proliferative capacity of the embryonic myocardium and most E2f3(-/-) mice die in utero or perinatally with hypoplastic ventricular walls and/or severe atrial and ventricular septal defects. A small fraction of the E2f3(-/-) neonates have hearts that appear grossly normal and they initially survive. However, these animals display ultrastructural defects in the cardiac muscle and ultimately die as a result of congestive heart failure. These data demonstrate a clear role for E2F3 in myocardial and cardiac function during both development and adulthood.