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Simple Summary: This study compared the muscle fiber composition of working and companion dog breeds to understand how their muscles adapt to breed-specific tasks. By analyzing the triceps brachii and biceps femoris muscles of 12 dogs, we found that working dogs had larger muscle fibers, a higher proportion of endurance-related fibers (types IIa and I), and more nuclei per fiber, which support strength and endurance. Companion dogs, on the other hand, had more fibers suited for short bursts of activity (type IIb) and fewer nuclei per fiber, suggesting slower muscle regeneration. These results highlight the role of selective breeding in shaping muscle structure and function in dogs. The structural and functional characteristics of skeletal muscle fibers play a crucial role in understanding the physical capabilities of dogs, particularly in relation to their breed-specific roles. This study aimed to compare the muscle fiber composition of working and companion dog breeds by analyzing the triceps brachii and biceps femoris muscles, focusing on fiber morphology, myosin heavy chain (MYH) isoform distribution, and nuclei per fiber. A total of 12 dogs, divided equally into working and companion breed groups, were used in this study. Muscle samples were collected post-mortem and prepared for histological analysis using cryosectioning. Immunohistochemical staining was employed to identify the expression of MYH isoforms, including MYH2, MYH4, and MYH7, which correspond to type IIa, IIb, and type I fibers, respectively. The results demonstrated significant differences between the two breed groups. Working dogs exhibited larger muscle fibers, a higher proportion of type IIa (MYH2) and type I (MYH7) fibers, and a greater number of nuclei per fiber, suggesting adaptations for endurance and strength. In contrast, companion dogs showed a higher proportion of type IIb (MYH4) fibers, indicative of their capacity for short bursts of activity rather than sustained exertion. Companion breeds also displayed a higher fiber density but fewer nuclei per fiber, which may contribute to slower muscle regeneration. These findings may provide insights into the muscle adaptations of dogs based on their breed-specific functional demands and highlight the importance of considering these differences in veterinary care and rehabilitation. The study underscores the influence of selective breeding on muscle structure and function in dogs and suggests further research into breed-specific muscle recovery mechanisms. [ABSTRACT FROM AUTHOR]

Cisplatin, a platinum-based anticancer drug used frequently in cancer treatment, causes skeletal muscle atrophy. It was predicted that the proteolytic pathway is enhanced as the mechanism of this atrophy. Therefore, we investigated whether a platinum-based anticancer drug affects the expression of the major proteins of skeletal muscle, myosin heavy chain (MyHC). Mice were injected with cisplatin or oxaliplatin for four consecutive days. C2C12 myotubes were treated using cisplatin and oxaliplatin. Administration of platinum-based anticancer drug reduced quadriceps mass and muscle strength compared to the control group. Protein levels of all MyHC isoforms were reduced in the platinum-based anticancer drug groups. However, only Myh2 (MyHC-IIa) gene expression in skeletal muscle of mice treated with platinum-based anticancer drugs was found to be reduced. Treatment of C2C12 myotubes with platinum-based anticancer drugs reduced the protein levels of all MyHCs, and treatment with the proteasome inhibitor MG-132 restored this reduction. The expression of Mef2c, which was predicted to act upstream of Myh2, was reduced in the skeletal muscle of mice treated systemically with platinum-based anticancer drug. Degradation of skeletal muscle MyHCs by proteasomes may be a factor that plays an important role in muscle mass loss in platinum-based anticancer drug-induced muscle atrophy.

Abstract Background Myosin heavy chain (MyHC) isoforms define the three major muscle fiber types in human extremity muscles. Slow beta/cardiac MyHC (MYH7) is expressed in type 1 muscle fibers. MyHC IIa (MYH2) and MyHC IIx (MYH1) are expressed in type 2A and 2B fibers, respectively. Whereas recessive MyHC IIa myopathy has been described in many cases, myopathy caused by dominant MYH2 variants is rare and has been described with clinical manifestations and muscle pathology in only one family and two sporadic cases. Methods We investigated three patients from one family with a dominantly inherited myopathy by clinical investigation, whole-genome sequencing, muscle biopsy, and magnetic resonance imaging (MRI). Results Three siblings, one woman and two men now 54, 56 and 66 years old, had experienced muscle weakness initially affecting the lower limbs from young adulthood. They have now generalized proximal muscle weakness affecting ambulation, but no ophthalmoplegia. Whole-genome sequencing identified a heterozygous MYH2 variant, segregating with the disease in the three affected individuals: c.5673 + 1G > C. Analysis of cDNA confirmed the predicted splicing defect with skipping of exon 39 and loss of residues 1860–1891 in the distal tail of the MyHC IIa, largely overlapping with the filament assembly region (aa1877–1905). Muscle biopsy in two of the affected individuals showed prominent type 1 muscle fiber predominance with only a few very small, scattered type 2A fibers and no type 2B fibers. The small type 2A fibers were frequently hybrid fibers with either slow MyHC or embryonic MyHC expression. The type 1 fibers showed variation in fiber size, internal nuclei and some structural alterations. There was fatty infiltration, which was also demonstrated by MRI. Conclusion Dominantly inherited MyHC IIa myopathy due to a splice defect causing loss of amino acids 1860–1891 in the distal tail of the MyHC IIa protein including part of the assembly competence domain. The myopathy is manifesting with slowly progressive muscle weakness without overt ophthalmoplegia and markedly reduced number and size of type 2 fibers.

• Three individuals with myopathy and a novel MYH2 splice-site variant. • Myopathy had autosomal dominant inheritance in a large four-generation pedigree. • EMG, muscle MRI, and muscle biopsy consistent with MYH2- associated myopathy. • RNAseq on fibroblasts demonstrated that the variant alters splicing. • Lack of ophthalmoplegia and congenital contractures expands the phenotype. MYH2 encodes MyHCIIa, a myosin heavy chain found in fast type 2A fibers. Pathogenic variants in this gene have previously been implicated in dominant and recessive forms of myopathy. Three individuals reported here are part of a family in which four generations of individuals are affected by a slowly progressive, predominantly proximal myopathy in an autosomal dominant inheritance pattern. Affected individuals in this family lacked classic features of an MYH2- associated myopathy such as congenital contractures and ophthalmoplegia. A novel variant, MYH2 c.5673+1G>C, was detected in the proband and subsequently found to segregate with disease in five additional family members. Further studies demonstrated that this variant affects splicing, resulting in novel transcripts. These data and muscle biopsy findings in the proband, indicate that this family's MYH2 variant is causative of their myopathy, adding to our understanding of the clinical and molecular characteristics of the disease. [ABSTRACT FROM AUTHOR]

Background: Myosin heavy chain (MyHC) isoforms define the three major muscle fiber types in human extremity muscles. Slow beta/cardiac MyHC (MYH7) is expressed in type 1 muscle fibers. MyHC IIa (MYH2) and MyHC IIx (MYH1) are expressed in type 2A and 2B fibers, respectively. Whereas recessive MyHC IIa myopathy has been described in many cases, myopathy caused by dominant MYH2 variants is rare and has been described with clinical manifestations and muscle pathology in only one family and two sporadic cases.Methods: We investigated three patients from one family with a dominantly inherited myopathy by clinical investigation, whole-genome sequencing, muscle biopsy, and magnetic resonance imaging (MRI).Results: Three siblings, one woman and two men now 54, 56 and 66 years old, had experienced muscle weakness initially affecting the lower limbs from young adulthood. They have now generalized proximal muscle weakness affecting ambulation, but no ophthalmoplegia. Whole-genome sequencing identified a heterozygous MYH2 variant, segregating with the disease in the three affected individuals: c.5673 + 1G > C. Analysis of cDNA confirmed the predicted splicing defect with skipping of exon 39 and loss of residues 1860-1891 in the distal tail of the MyHC IIa, largely overlapping with the filament assembly region (aa1877-1905). Muscle biopsy in two of the affected individuals showed prominent type 1 muscle fiber predominance with only a few very small, scattered type 2A fibers and no type 2B fibers. The small type 2A fibers were frequently hybrid fibers with either slow MyHC or embryonic MyHC expression. The type 1 fibers showed variation in fiber size, internal nuclei and some structural alterations. There was fatty infiltration, which was also demonstrated by MRI.Conclusion: Dominantly inherited MyHC IIa myopathy due to a splice defect causing loss of amino acids 1860-1891 in the distal tail of the MyHC IIa protein including part of the assembly competence domain. The myopathy is manifesting with slowly progressive muscle weakness without overt ophthalmoplegia and markedly reduced number and size of type 2 fibers. [ABSTRACT FROM AUTHOR]

Abstract The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. MYH2-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Additional myopathological abnormalities have included rimmed vacuoles containing small p62 positive inclusions, 15–20 nm tubulofilaments, minicores and dystrophic changes. We report an adult patient with late-pediatric onset MYH2-myopathy caused by two heterozygous pathogenic variants: c.3331C>T, p.Gln1111* predicted to result in truncation of the proximal tail region of MyHC-IIA, and c.1546T>G, p.Phe516Val, affecting a highly conserved amino acid within the highly conserved catalytic motor head relay loop. This missense variant is predicted to result in a less compact loop domain and in turn could affect the protein affinity state. The patient’s genotype is accompanied by a novel myopathological phenotype characterized by centralized large myofilamentous tangles associated with clusters of nemaline rods, and ring fibers, in addition to the previously reported rimmed vacuoles, paucity and atrophy of type 2A fibers. Electron microscopy demonstrated wide areas of disorganized myofibrils which were oriented in various planes of direction and entrapped multiple nemaline rods, as corresponding to the large tangles with rods seen on light microscopy. Nemaline rods were rarely observed also in nuclei. We speculate that the mutated MyHC-IIA may influence myofibril disorganization. While nemaline rods have been described in myopathies caused by pathogenic variants in genes encoding several sarcomeric proteins, to our knowledge, nemaline rods have not been previously described in MYH2-myopathy.

Background: Postural tremor is an uncommon and often overlooked phenotype in skeletal myopathy, which may lead to diagnostic delays., Case Report: A 21-year-old man presented with adolescent onset postural hand tremor as the initial symptom, followed by mild limb muscle weakness. Neurological examination showed restricted ocular motility without diplopia and myopathic facial appearance. A muscle biopsy showed a decrease in type 2A fibers. Whole-exome sequencing identified two novel compound heterozygous variants in MYH2 gene (NM_017534.6): c.505+2T>C and c.3565 del C. The diagnosis was further validated via bioinformatics analysis and confirmed through familial co-segregation by Sanger sequencing., Discussion: This report expands the mutational and phenotypic spectrum of MYH2 -associated myopathy. We suggest that in the differential diagnosis of tremor, besides common neurogenic causes, myogenic etiology should also be considered., Highlights: Hand tremor in this case expands the phenotype of MYH2-associated myopathy, enhancing our understanding of tremor origins. It underscores the importance of nuanced clinical assessment and genetic screening in complex tremor disorders., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Abstract Background Immunohistochemical studies of hearts from the lesser spotted dogfish, Scyliorhinus canicula (Chondrichthyes) revealed that the pan-myosin heavy chain (pan-MyHC) antibody MF20 homogeneously labels all the myocardium, while the pan-MyHC antibody A4.1025 labels the myocardium of the inflow (sinus venosus and atrium) but not the outflow (ventricle and conus arteriosus) cardiac segments, as opposed to other vertebrates. We hypothesized that the conventional pattern of cardiac MyHC isoform distribution present in most vertebrates, i.e. MYH6 in the inflow and MYH7 in the outflow segments, has evolved from a primitive pattern that persists in Chondrichthyes. In order to test this hypothesis, we conducted protein detection techniques to identify the MyHC isoforms expressed in adult dogfish cardiac segments and to assess the pan-MyHC antibodies reactivity against the cardiac segments of representative species from different vertebrate groups. Results Western and slot blot results confirmed the specificity of MF20 and A4.1025 for MyHC in dogfish and their differential reactivity against distinct myocardial segments. HPLC-ESI-MS/MS and ESI-Quadrupole-Orbitrap revealed abundance of MYH6 and MYH2 in the inflow and of MYH7 and MYH7B in the outflow segments. Immunoprecipitation showed higher affinity of A4.1025 for MYH2 and MYH6 than for MYH7 and almost no affinity for MYH7B. Immunohistochemistry showed that A4.1025 signals are restricted to the inflow myocardial segments of elasmobranchs, homogeneous in all myocardial segments of teleosts and acipenseriforms, and low in the ventricle of polypteriforms. Conclusions The cardiac inflow and outflow segments of the dogfish show predominance of fast- and slow-twitch MyHC isoforms respectively, what can be considered a synapomorphy of gnathostomes. The myocardium of the dogfish contains two isomyosins (MYH2 and MYH7B) not expressed in the adult heart of other vertebrates. We propose that these isomyosins lost their function in cardiac contraction during the evolution of gnathostomes, the later acquiring a regulatory role in myogenesis through its intronic miRNA. Loss of MYH2 and MYH7B expression in the heart possibly occurred before the origin of Osteichthyes, being the latter reacquired in polypteriforms. We raise the hypothesis that the slow tonic MYH7B facilitates the peristaltic contraction of the conus arteriosus of fish with a primitive cardiac anatomical design and of the vertebrate embryo.

The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. MYH2-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Additional myopathological abnormalities have included rimmed vacuoles containing small p62 positive inclusions, 15–20 nm tubulofilaments, minicores and dystrophic changes. We report an adult patient with late-pediatric onset MYH2-myopathy caused by two heterozygous pathogenic variants: c.3331C>T, p.Gln1111* predicted to result in truncation of the proximal tail region of MyHC-IIA, and c.1546T>G, p.Phe516Val, affecting a highly conserved amino acid within the highly conserved catalytic motor head relay loop. This missense variant is predicted to result in a less compact loop domain and in turn could affect the protein affinity state. The patient's genotype is accompanied by a novel myopathological phenotype characterized by centralized large myofilamentous tangles associated with clusters of nemaline rods, and ring fibers, in addition to the previously reported rimmed vacuoles, paucity and atrophy of type 2A fibers. Electron microscopy demonstrated wide areas of disorganized myofibrils which were oriented in various planes of direction and entrapped multiple nemaline rods, as corresponding to the large tangles with rods seen on light microscopy. Nemaline rods were rarely observed also in nuclei. We speculate that the mutated MyHC-IIA may influence myofibril disorganization. While nemaline rods have been described in myopathies caused by pathogenic variants in genes encoding several sarcomeric proteins, to our knowledge, nemaline rods have not been previously described in MYH2-myopathy. [ABSTRACT FROM AUTHOR]

Abstract Background Hereditary myosin myopathies are a group of rare muscle disorders, caused by mutations in genes encoding for skeletal myosin heavy chains (MyHCs). MyHCIIa is encoded by MYH2 and is expressed in fast type 2A and 2B muscle fibers. MYH2 mutations are responsible for an autosomal dominant (AD) progressive myopathy, characterized by the presence of rimmed vacuoles and by a reduction in the number and size of type 2A fibers, and a recessive early onset myopathy characterized by complete loss of type 2A fibers. Recently, a patient with a homozygous mutation but presenting a dominant phenotype has been reported. Methods The patient was examined thoroughly and two muscle biopsies were performed through the years. NGS followed by confirmation in Sanger sequencing was used to identify the genetic cause. Results We describe the second case presenting with late‐onset ophthalmoparesis, ptosis, diffuse muscle weakness, and histopathological features typical for AD forms but with a recessive MYH2 genotype. Conclusion This report contributes to expand the clinical and genetic spectrum of MYH2 myopathies and to increase the awareness of these very rare diseases.

Background: Hereditary myosin myopathies are a group of rare muscle disorders, caused by mutations in genes encoding for skeletal myosin heavy chains (MyHCs). MyHCIIa is encoded by MYH2 and is expressed in fast type 2A and 2B muscle fibers. MYH2 mutations are responsible for an autosomal dominant (AD) progressive myopathy, characterized by the presence of rimmed vacuoles and by a reduction in the number and size of type 2A fibers, and a recessive early onset myopathy characterized by complete loss of type 2A fibers. Recently, a patient with a homozygous mutation but presenting a dominant phenotype has been reported. Methods: The patient was examined thoroughly and two muscle biopsies were performed through the years. NGS followed by confirmation in Sanger sequencing was used to identify the genetic cause. Results: We describe the second case presenting with late‐onset ophthalmoparesis, ptosis, diffuse muscle weakness, and histopathological features typical for AD forms but with a recessive MYH2 genotype. Conclusion: This report contributes to expand the clinical and genetic spectrum of MYH2 myopathies and to increase the awareness of these very rare diseases. [ABSTRACT FROM AUTHOR]

Muscle–bone interactions during fracture healing are rarely known. Here we investigated the presence and significance of myosin heavy chain 2 (MYH2), a component of myosin derived from muscles, in fracture healing. We collected five hematoma and seven soft callus tissues from patients with distal radius fractures patients, randomly selected three of them, and performed a liquid chromatography–mass spectrometry (LC-MS) proteomics analysis. Proteomic results were validated by histological observation, immunohistochemistry, and immunofluorescence for MYH2 expression. These findings were further confirmed in a murine femoral fracture model in vivo and investigated using various methods in vitro. The LC-MS proteomics analysis showed that MYH proteins were enriched in human soft calluses compared to hematoma. Notably, MYH2 protein is upregulated as high rank in each soft callus. The histological examination showed that MYH2 expression was elevated in hypertrophic chondrocytes within the human soft callus. Consistent with human data, Myh2 were significantly co-localized with Sox9 in hypertrophic chondrocytes of murine femoral fracture, in comparison to pre-hypertrophic and proliferating chondrocytes. Soluble MYH2 protein treatment increased MMP13 and RUNX2 expression in chondrocytes. In soluble MYH2 treatment, proliferation of chondrocytes was not altered, but the osteogenic and chondrogenic features of chondrocytes increased and decreased during differentiation, respectively. These findings indicate the potential of soluble MYH2 protein as a promising therapeutic strategy for promoting endochondral bone formation in chondrocytes following fracture. • MYH2 is substantially higher in soft callus than in hematoma. • MYH2 and SOX9 are more significantly co-localized in hypertrophic chondrocytes of soft callus. • MYH2 treatment leads to an increase in the osteogenic differentiation of chondrocytes and decreases in chondrogenic differentiation. [ABSTRACT FROM AUTHOR]

Meat quality is one of the most important economic traits in pig breeding. It has been reported that the composition of type II muscle fibers is correlated with meat quality in pigs. Type II muscle fibers contain three isoforms, IIa, IIb and IIx, which contain specific myofibrillar proteins MYH2, MYH4 and MYH1, respectively. In this study, the expression levels of MYH1, MYH2, and MYH4 genes in the Longissimus thoracis (LT) muscle were measured in 114 Yorkshire pigs. Further, the correlations between the expression level of MYH genes and the meat quality traits of intramuscular fat, drip loss, water-holding capacity and postmortem pH values were analyzed. The results showed that the expression level of MYH2 was positively correlated with the intramuscular fat (R= 0.20, P24h ; R=-0.28, P

Highlights • MYH2 mutations cause dominant and recessive myopathies with ophthalmoplegia. • Dominant mutations cause progressive proximal weakness with rimmed vacuoles. • Recessive mutations cause congenital myopathy with reduced MyHCIIa expression. • We describe a recessive MYH2 mutation associated with a dominant phenotype. Abstract Mutations in MYH2 that encodes myosin heavy chain IIa cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with ophthalmoplegia and progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, patients with recessive MYH2 mutations have early onset, non-progressive, diffuse weakness and ophthalmoplegia. Muscle biopsy reveals near or complete absence of type 2A fibers with no vacuole or inclusion pathology. We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient's disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246His homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies. [ABSTRACT FROM AUTHOR]

Dystocia is an obstetrical emergency, and primary uterine inertia (PUI) is the major etiological reason among the more prevalent maternal causes in dogs. The present study involved the relative expression analysis of genes associated with myometrial contraction in medium-sized dog breeds with uterine inertia. Dogs without any progress in the parturition process even after four hours of the onset of labor and the absence of uterine contractions were considered to have complete primary uterine inertia (CPUI, n = 9). Dogs that had expelled at least one fetus and made no further progress in parturition in the absence of active uterine contraction were considered to be experiencing partial primary uterine inertia (PPUI, n = 6). Dogs with the fetal cause of dystocia (FCD), i.e., obstructive dystocia, were taken as the third (n = 7) group. Uterine tissue samples were collected during cesarean section in each group, RNA was isolated, and the relative expression of myometrial ACTA2, ACTG2, MLCK4 , MYH2, and PKC genes was analyzed. The MLCK4 gene expression was downregulated in CPUI (P ≤ 0.05) and PPUI (P ≤ 0.01) when compared to FCD. The MYH2 gene expression was downregulated in PPUI in comparison to CPUI (P ≤ 0.01) and FCD (P ≤ 0.05). The PKC gene expression was upregulated in PPUI in comparison to FCD and CPUI (P ≤ 0.05). The downregulation of MLCK4 and MYH2 gene expressions recorded in PPUI indicated the possibility of myometrial defects. The possibility of myometrial defects was also observed in CPUI, but to a lesser degree, suggesting other etiologies. • MLCK4 down-regulation -might be an etiological factor in primary uterine inertia. • Downregulation of MYH 2 was observed in partial primary uterine inertia. • Upregulation of PKC might contribute to the partial primary uterine inertia. [ABSTRACT FROM AUTHOR]

A 7-week-old infant presented with persistent noisy breathing and aspirations during swallowing. Neurological examination and brain MRI were normal. His 12-year-old brother underwent pneumonectomy at the age of 10 years due to recurrent aspirations leading to severe lung damage. The older brother developed subsequently ophthalmoplegia and nystagmus along with mild weakness of the neck flexors and proximal muscles. Exome analysis revealed homozygosity for a novel truncating mutation p.G800fs27* in the Myosin Heavy Chain 2 ( MYH2 ) gene in both brothers, while parents and an unaffected sibling were heterozygous. A muscle biopsy from the older brother showed absence of type-2 muscle fibers and predominance of type-1 fibers. The aspirations causing pneumonia likely result from weakness of the laryngeal muscles, normally rich in type-2 fibers. The findings expand the phenotypic spectrum of MYH2 deficiency. MYH2 mutations should be included in the differential diagnosis of infants presenting with recurrent aspirations. [ABSTRACT FROM AUTHOR]

Myosin heavy chain (MyHC) is a major structural component of the striated muscle contractile apparatus. In adult human limb skeletal muscle, there are three major MyHC isoforms, slow/beta cardiac MyHC, MyHC IIa and MHC IIx, which are important for the functional characteristics of different muscle fiber types. Hereditary myosin myopathies have emerged as an important group of diseases with variable clinical and morphological expression dependent on the mutated isoform, and also the type and location of the mutation. Myosin myopathy with external ophthalmoplegia is associated with mutations in MYH2, encoding for MyHC IIa that is mainly expressed in type 2A muscle fibers and is inherited in dominant as well as recessive manner. We present a family with myopathy with early onset proximal muscle weakness, facial muscle involvement and ophthalmoplegia. Muscle biopsy demonstrated lack of type 2A muscle fibers and genetic work up demonstrated that the disease was caused by a novel recessive MYH2 mutation: c.1009-1G>A resulting in skipping of exon 12, which is predicted to result in a frame shift and introducing at premature stop codon at position 347 (p.Ser337Leufs*11). [ABSTRACT FROM AUTHOR]

An MYH2 mutation p.( Glu706Lys) was originally described in a family with autosomal dominant inheritance, where the affected family members presented with multiple congenital contractures and ophthalmoplegia, progressing to a proximal myopathy in adulthood. Another patient with a dominant mutation p.( Leu1870Pro) was described, presenting as a congenital myopathy with ophthalmoplegia. Here, we present a patient with symptoms beginning at age 16 years, of prominent distal but also proximal weakness, bulbar involvement and ophthalmoplegia. Initially, clinically classified as oculopharyngodistal myopathy, the patient was found to carry a novel, de novo MYH2 mutation c. 5630T>C p.( Leu1877Pro). This expands the phenotype of dominant MYH2 myopathies with the clinical phenotype overlapping the oculopharyngodistal myopathy spectrum. [ABSTRACT FROM AUTHOR]

Abstract: Congenital myopathy related to mutations in myosin MyHC IIa gene (MYH2) is a rare neuromuscular disease. A single dominant missense mutation has been reported so far in a family in which the affected members had congenital joint contractures at birth, external ophthalmoplegia and proximal muscle weakness. Afterward only additional 4 recessive mutations have been identified in 5 patients presenting a mild non-progressive early-onset myopathy associated with ophthalmoparesis. We report a new de novo MYH2 missense mutation in a baby affected by a congenital myopathy characterized by severe dysphagia, respiratory distress at birth and external ophthalmoplegia. We describe clinical, histopathological and muscle imaging findings expanding the clinical and genetic spectrum of MYH2-related myopathy. [Copyright &y& Elsevier]

We recently described a new autosomal dominant myopathy (OMIM#605637) associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene (MYH2). In this study, we performed mutation analysis of MYH2 in eight Swedish patients with familial myopathy of unknown cause. In two of the eight index cases, we identified novel heterozygous missense mutations in MYH2, one in each case: V970I and L1061V. The mutations were located in subfragment 2 of the MyHC and they changed highly conserved residues. Most family members carrying the mutations had signs and symptoms consisting mainly of mild muscle weakness and myalgia. In addition, we analyzed the extent and distribution of nucleotide variation in MYH2 in 50 blood donors, who served as controls, by the complete sequencing of all 38 exons comprising the coding region. We identified only six polymorphic sites, five of which were synonymous polymorphisms. One variant, which occurred at an allele frequency of 0.01, was identical to the L1061V that was also found in one of the families with myopathy. The results of the analysis of normal variation indicate that there is strong selective pressure against mutations in MYH2. On the basis of these results, we suggest that MyHC genes should be regarded as candidate genes in cases of hereditary myopathies of unknown etiology.European Journal of Human Genetics (2005) 13, 617-622. doi:10.1038/sj.ejhg.5201375 Published online 2 March 2005 [ABSTRACT FROM AUTHOR]

Fatty acid (FA) composition is one of the most important parameters for the assessment of meat quality in pigs. The FA composition in pork can also affect human health. Our aim was to identify quantitative trait loci (QTLs) and positional candidate genes affecting the FA profile of the longissimus dorsi muscle in a large F2 intercross between Landrace and Korean native pigs comprising 1105 F2 progeny by genome-wide association studies (GWAS) and post-GWAS high-resolution mapping analyses. We performed GWAS using the PorcineSNP60K BeadChip and a linear mixed model. Four genome-wide significant QTL regions in SSC8, SSC12, SSC14, and SSC16 were detected (p < 2.53 × 10−7). Several co-localizations of QTLs in SSC12 for oleic acid, linoleic acid, arachidonic acid, monounsaturated FAs, polyunsaturated FAs, and the polyunsaturated/saturated FA ratio were observed. To refine the QTL region in SSC12, a linkage and linkage disequilibrium analysis was applied and could narrow down the critical region to a 0.749 Mb region. Of the genes in this region, GAS7, MYH2, and MYH3 were identified as strong novel candidate genes based on further conditional association analyses. These findings provide a novel insight into the genetic basis of FA composition in pork and could contribute to the improvement of pork quality. [ABSTRACT FROM AUTHOR]

To mimic skeletal muscle tissues in vitro , native and transgenic spider silk/silkworm silks were seeded with C2C12 myoblasts to observe if these three-dimensional substrates are preferable to a traditional two-dimensional polystyrene cell culture surface. Silks were wound around an acrylic chassis to produce a novel, three-dimensional cell culture device with suspended muscle fibers that genetically and morphologically resemble native skeletal muscle tissue. The transgenic spider silk/silkworm silk has never before been studied for this application. Genetic expression verified skeletal muscle lineage and differentiation, while fluorescent imaging verified contractile protein synthesis. Genetic analysis also revealed an increase in expression of the Myh2 contractile protein gene on silkworm silks, particularly on the transgenic silk. Mechanical properties and protein secondary structure content of the silks indicated correlation between substrate properties and Myh2 gene expression. This increase in contractile protein gene expression suggests that biologically derived silk substrates that are suspended may be a preferable substrate for in vitro muscle modeling because of the proteinaceous character and mechanical flexibility of the silk.

Background: Immunohistochemical studies of hearts from the lesser spotted dogfish, Scyliorhinus canicula (Chondrichthyes) revealed that the pan-myosin heavy chain (pan-MyHC) antibody MF20 homogeneously labels all the myocardium, while the pan-MyHC antibody A4.1025 labels the myocardium of the inflow (sinus venosus and atrium) but not the outflow (ventricle and conus arteriosus) cardiac segments, as opposed to other vertebrates. We hypothesized that the conventional pattern of cardiac MyHC isoform distribution present in most vertebrates, i.e. MYH6 in the inflow and MYH7 in the outflow segments, has evolved from a primitive pattern that persists in Chondrichthyes. In order to test this hypothesis, we conducted protein detection techniques to identify the MyHC isoforms expressed in adult dogfish cardiac segments and to assess the pan-MyHC antibodies reactivity against the cardiac segments of representative species from different vertebrate groups. Results: Western and slot blot results confirmed the specificity of MF20 and A4.1025 for MyHC in dogfish and their differential reactivity against distinct myocardial segments. HPLC-ESI-MS/MS and ESI-Quadrupole-Orbitrap revealed abundance of MYH6 and MYH2 in the inflow and of MYH7 and MYH7B in the outflow segments. Immunoprecipitation showed higher affinity of A4.1025 for MYH2 and MYH6 than for MYH7 and almost no affinity for MYH7B. Immunohistochemistry showed that A4.1025 signals are restricted to the inflow myocardial segments of elasmobranchs, homogeneous in all myocardial segments of teleosts and acipenseriforms, and low in the ventricle of polypteriforms. Conclusions: The cardiac inflow and outflow segments of the dogfish show predominance of fast- and slow-twitch MyHC isoforms respectively, what can be considered a synapomorphy of gnathostomes. The myocardium of the dogfish contains two isomyosins (MYH2 and MYH7B) not expressed in the adult heart of other vertebrates. We propose that these isomyosins lost their function in cardiac contraction during the evolution of gnathostomes, the later acquiring a regulatory role in myogenesis through its intronic miRNA. Loss of MYH2 and MYH7B expression in the heart possibly occurred before the origin of Osteichthyes, being the latter reacquired in polypteriforms. We raise the hypothesis that the slow tonic MYH7B facilitates the peristaltic contraction of the conus arteriosus of fish with a primitive cardiac anatomical design and of the vertebrate embryo. [ABSTRACT FROM AUTHOR]

Here, we describe the case of a motor developmental disorder associated with intellectual disability accompanied by MYH2 mutations (c.2266G>A and c.4258C>T) in a female child in China. Her initial detailed functional rehabilitation evaluation gauged motor skills, balance, verbal language, and daily living skills. A general therapy plan was then established to enhance balance, muscle strength in the lower extremities, walking, gross and fine motor function, and family education. Clinicians and therapists later modified her rehabilitation regimen after her MYH2 mutations were identified by adding specific mobility and endurance exercise to the original plan. The clinical remission of myopathy with MYH2 missense mutations was observed in the patient after this targeted rehabilitation, indicating that precision therapy is very effective for developing a suitable rehabilitation program for patients with unexplained myopathies., Competing Interests: None.