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Head and Neck Pathology Dec 2015Rhabdomyosarcoma is a relatively common soft tissue sarcoma that frequently affects children and adolescents and may involve the head and neck. Rhabdomyosarcoma is... (Review)
Review
Rhabdomyosarcoma is a relatively common soft tissue sarcoma that frequently affects children and adolescents and may involve the head and neck. Rhabdomyosarcoma is defined by skeletal muscle differentiation which can be suggested by routine histology and confirmed by immunohistochemistry for the skeletal muscle-specific markers myogenin or myoD1. At the same time, it must be remembered that when it comes to head and neck malignancies, skeletal muscle differentiation is not limited to rhabdomyosarcoma. A lack of awareness of this phenomenon could lead to misdiagnosis and, subsequently, inappropriate therapeutic interventions. This review focuses on malignant neoplasms of the head and neck other than rhabdomyosarcoma that may exhibit rhabdomyoblastic differentiation, with an emphasis on strategies to resolve the diagnostic dilemmas these tumors may present. Axiomatically, no primary central nervous system tumors will be discussed.
Topics: Head and Neck Neoplasms; Humans; Muscle, Skeletal; Neoplasms, Muscle Tissue; Rhabdomyosarcoma
PubMed: 25757816
DOI: 10.1007/s12105-015-0624-2 -
Journal of Cachexia, Sarcopenia and... Feb 2024Muscle aging is associated with a consistent decrease in the ability of muscle tissue to regenerate following intrinsic muscle degradation, injury or overuse....
BACKGROUND
Muscle aging is associated with a consistent decrease in the ability of muscle tissue to regenerate following intrinsic muscle degradation, injury or overuse. Age-related imbalance of protein synthesis and degradation, mainly regulated by AKT/mTOR pathway, leads to progressive loss of muscle mass. Maintenance of anabolic and regenerative capacities of skeletal muscles may be regarded as a therapeutic option for sarcopenia and other muscle wasting diseases. Our previous studies have demonstrated that BIO101, a pharmaceutical grade 20-hydroxyecdysone, increases protein synthesis through the activation of MAS receptor involved in the protective arm of renin-angiotensin-aldosterone system. The purpose of the present study was to assess the anabolic and pro-differentiating properties of BIO101 on C2C12 muscle cells in vitro and to investigate its effects on adult and old mice models in vivo.
METHODS
The effects of BIO101 on C2C12 differentiation were assessed using myogenic transcription factors and protein expression of major kinases of AKT/mTOR pathway by Western blot. The in vivo effects of BIO101 have been investigated in BIO101 orally-treated (50 mg/kg/day) adult mice (3 months) for 28 days. To demonstrate potential beneficial effect of BIO101 treatment in a sarcopenic mouse model, we use orally treated 22-month-old C57Bl6/J mice, for 14 weeks with vehicle or BIO101. Mice body and muscle weight were recorded. Physical performances were assessed using running capacity and muscle contractility tests.
RESULTS
Anabolic properties of BIO101 were confirmed by the rapid activation of AKT/mTOR, leading to an increase of C2C12 myotubes diameters (+26%, P < 0.001). Pro-differentiating effects of BIO101 on C2C12 myoblasts were revealed by increased expression of muscle-specific differentiation transcription factors (MyoD, myogenin), resulting in increased fusion index and number of nuclei per myotube (+39% and +53%, respectively, at day 6). These effects of BIO101 were like those of angiotensin (1-7) and were abolished with the use of A779, a MAS receptor specific antagonist. Chronic BIO101 oral treatment induced AKT/mTOR activation and anabolic effects accompanied with improved physical performances in adult and old animals (maximal running distance and maximal running velocity).
CONCLUSIONS
Our data suggest beneficial anabolic and pro-differentiating effects of BIO101 rendering BIO101 a potent drug candidate for treating sarcopenia and possibly other muscle wasting disorders.
Topics: Mice; Animals; Sarcopenia; Proto-Oncogene Proteins c-akt; Muscle, Skeletal; Muscular Diseases; Muscular Atrophy; TOR Serine-Threonine Kinases; Myoblasts; Transcription Factors
PubMed: 38064183
DOI: 10.1002/jcsm.13326 -
Molecular Metabolism May 2023Skeletal muscle regeneration is markedly impaired during aging. How adult muscle stem cells contribute to this decrease in regenerative capacity is incompletely...
OBJECTIVE
Skeletal muscle regeneration is markedly impaired during aging. How adult muscle stem cells contribute to this decrease in regenerative capacity is incompletely understood. We investigated mechanisms of age-related changes in myogenic progenitor cells using the tissue-specific microRNA 501.
METHODS
Young and old C57Bl/6 mice were used (3 months or 24 months of age, respectively) with or without global or tissue-specific genetic deletion of miR-501. Muscle regeneration was induced using intramuscular cardiotoxin injection or treadmill exercise and analysed using single cell and bulk RNA sequencing, qRT-PCR and immunofluorescence. Muscle fiber damage was assessed with Evan`s blue dye (EBD). In vitro analysis was performed in primary muscle cells obtained from mice and humans.
RESULTS
Single cell sequencing revealed myogenic progenitor cells in miR-501 knockout mice at day 6 after muscle injury that are characterized by high levels of myogenin and CD74. In control mice these cells were less in number and already downregulated after day 3 of muscle injury. Muscle from knockout mice had reduced myofiber size and reduced myofiber resilience to injury and exercise. miR-501 elicits this effect by regulating sarcomeric gene expression through its target gene estrogen-related receptor gamma (Esrrg). Importantly, in aged skeletal muscle where miR-501 was significantly downregulated and its target Esrrg significantly upregulated, the number of myog/CD74 cells during regeneration was upregulated to similar levels as observed in 501 knockout mice. Moreover, myog/CD74-aged skeletal muscle exhibited a similar decrease in the size of newly formed myofibers and increased number of necrotic myofibers after injury as observed in mice lacking miR-501.
CONCLUSIONS
miR-501 and Esrrg are regulated in muscle with decreased regenerative capacity and loss of miR-501 is permissive to the appearance of CD74 myogenic progenitors. Our data uncover a novel link between the metabolic transcription factor Esrrg and sarcomere formation and demonstrate that stem cell heterogeneity in skeletal muscle during aging is under miRNA control. Targeting Esrrg or myog/CD74 progenitor cells might improve fiber size and myofiber resilience to exercise in aged skeletal muscle.
Topics: Adult; Aged; Animals; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Muscle, Skeletal; Myogenin; Regeneration; Stem Cells
PubMed: 36907509
DOI: 10.1016/j.molmet.2023.101704 -
Journal of Ginseng Research Jan 2024Skeletal muscle (SM) is the largest organ of the body and is largely responsible for the metabolism required to maintain body functions. Furthermore, the maintenance of... (Review)
Review
Skeletal muscle (SM) is the largest organ of the body and is largely responsible for the metabolism required to maintain body functions. Furthermore, the maintenance of SM is dependent on the activation of muscle satellite (stem) cells (MSCs) and the subsequent proliferation and fusion of differentiating myoblasts into mature myofibers (myogenesis). Natural compounds are being used as therapeutic options to promote SM regeneration during aging, muscle atrophy, sarcopenia, cachexia, or obesity. In particular, ginseng-derived compounds have been utilized in these contexts, though ginsenoside Rg1 is mostly used for SM mass management. These compounds primarily function by activating the Akt/mTOR signaling pathway, upregulating myogenin and MyoD to induce muscle hypertrophy, downregulating atrophic factors (atrogin1, muscle ring-finger protein-1, myostatin, and mitochondrial reactive oxygen species production), and suppressing the expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cachexia. Ginsenoside compounds are also used for obesity management, and their anti-obesity effects are attributed to peroxisome proliferator activated receptor gamma (PPARγ) inhibition, AMPK activation, glucose transporter type 4 (GLUT4) translocation, and increased phosphorylations of insulin resistance (IR), insulin receptor substrate-1 (IRS-1), and Akt. This review was undertaken to provide an overview of the use of ginseng-related compounds for the management of SM-related disorders.
PubMed: 38223826
DOI: 10.1016/j.jgr.2023.06.003 -
Acta Medica Indonesiana Jan 2023Leiomyosarcoma commonly occurs in the abdomen, retroperitoneum, large blood vessels, and uterus[1]. Cardiac leiomyosarcoma is a rare and highly aggressive sarcoma. We...
Leiomyosarcoma commonly occurs in the abdomen, retroperitoneum, large blood vessels, and uterus[1]. Cardiac leiomyosarcoma is a rare and highly aggressive sarcoma. We reported a case of a 63-year-old male with pulmonary artery leiomyosarcoma. Transthoracic echocardiography showed a large 4.4×2.3 cm hypoechoic mass in the right ventricular outflow tract and pulmonary artery. Computed tomography pulmonary angiography showed a filling defect in a similar location. The initial impression was PE, but a tumor was not ruled out. An emergency surgery was performed due to progressively worse chest distress and dyspnea. A yellow mass that had adhered to the ventricular septum and pulmonary artery wall was detected to be compressing the pulmonary valve. Immunohistochemistry confirmed tumor cells positive staining for Desmin and smooth muscle actin and negative staining for S-100, CD34, myogenin, or myoglobin, and KI67(+)80%, indicating leiomyosarcoma. Pulmonary leiomyosarcoma showed a side-inserted heart chamber filling defect in CTA and should be excised when the patient suddenly deteriorated.
Topics: Male; Female; Humans; Middle Aged; Leiomyosarcoma; Pulmonary Artery; Lung; Lung Neoplasms; Immunohistochemistry
PubMed: 36999261
DOI: No ID Found -
Head and Neck Pathology Mar 2020Biphenotypic sinonasal sarcoma is an anatomically restricted low-grade malignant neoplasm with dual neural and myogenic differentiation composed of a monotonous... (Review)
Review
Biphenotypic sinonasal sarcoma is an anatomically restricted low-grade malignant neoplasm with dual neural and myogenic differentiation composed of a monotonous population of spindled cells with herringbone/fascicular architecture. These tumors demonstrate a unique immunoprofile with relatively consistent S100-protein and actin expression in conjunction with more variable desmin, myogenin and myoD1 staining. SOX10 is uniformly negative. Genetically, the majority of tumors harbor PAX3-MAML3 fusions, with alternate PAX3 partners including FOXO1, NCOA1, NCOA2 and WWTR1. Although the differential diagnosis of BSNS is broad, careful morphologic inspection together with targeted ancillary studies is often sufficient to arrive at the correct diagnosis. As these tumors have significant local recurrence rates but lack metastatic potential, awareness and accurate diagnosis of this rare and newly described neoplasm is critical for appropriate management.
Topics: Biomarkers, Tumor; Diagnosis, Differential; Humans; Paranasal Sinus Neoplasms; Sarcoma; Soft Tissue Neoplasms
PubMed: 31950469
DOI: 10.1007/s12105-019-01092-4 -
Oncotarget Nov 2017N-Myc downstream-regulated gene 4 () plays an important role in biological processes and pathogenesis, but its function in muscle development is unclear. In this study,...
N-Myc downstream-regulated gene 4 () plays an important role in biological processes and pathogenesis, but its function in muscle development is unclear. In this study, we investigated the function of the gene in the regulation of myogenic differentiation. NDRG4 expression is upregulated during muscle regeneration and C2C12 myoblast differentiation. Gain and loss of function studies revealed that NDRG4 dramatically promotes expression of myogenic differentiation factor (), myogenin (), and myosin heavy chain () genes and myotube formation. Mechanistically, the binding of NDRG4 to carboxyl-terminal modulator protein (CTMP) abates the interaction of CTMP and protein kinase B (Akt) and increases the phosphorylation of Akt and cAMP response element binding protein (CREB), which leads to increased expression of myogenic genes. Our results reveal that NDRG4 promotes myogenic differentiation via Akt/CREB activation.
PubMed: 29254199
DOI: 10.18632/oncotarget.21591 -
Cells Mar 2020NF-YA, the regulatory subunit of the trimeric transcription factor (TF) NF-Y, is regulated by alternative splicing (AS) generating two major isoforms, "long" (NF-YAl)...
NF-YA, the regulatory subunit of the trimeric transcription factor (TF) NF-Y, is regulated by alternative splicing (AS) generating two major isoforms, "long" (NF-YAl) and "short" (NF-YAs). Muscle cells express NF-YAl. We ablated exon 3 in mouse C2C12 cells by a four-guide CRISPR/Cas9n strategy, obtaining clones expressing exclusively NF-YAs (C2-YAl-KO). C2-YAl-KO cells grow normally, but are unable to differentiate. Myogenin and-to a lesser extent, MyoD- levels are substantially lower in C2-YAl-KO, before and after differentiation. Expression of the fusogenic Myomaker and Myomixer genes, crucial for the early phases of the process, is not induced. Myomaker and Myomixer promoters are bound by MyoD and Myogenin, and Myogenin overexpression induces their expression in C2-YAl-KO. NF-Y inactivation reduces MyoD and Myogenin, but not directly: the Myogenin promoter is CCAAT-less, and the canonical CCAAT of the MyoD promoter is not bound by NF-Y in vivo. We propose that NF-YAl, but not NF-YAs, maintains muscle commitment by indirectly regulating Myogenin and MyoD expression in C2C12 cells. These experiments are the first genetic evidence that the two NF-YA isoforms have functionally distinct roles.
Topics: Animals; Base Sequence; CCAAT-Binding Factor; CRISPR-Cas Systems; Cell Differentiation; Cell Fusion; Cell Line; Clone Cells; Exons; Gene Expression Regulation; Mice; Muscle Fibers, Skeletal; MyoD Protein; Myogenin; Protein Isoforms; Transcription Factors
PubMed: 32214056
DOI: 10.3390/cells9030789 -
Experimental Physiology Dec 2023What is the central question of this study? Does the hormone Klotho affect the myogenic response of muscle cells to mechanical loading or exercise? What is the main...
NEW FINDINGS
What is the central question of this study? Does the hormone Klotho affect the myogenic response of muscle cells to mechanical loading or exercise? What is the main finding and its importance? Klotho prevents direct, mechanical activation of genes that regulate muscle differentiation, including genes that encode the myogenic regulatory factor myogenin and proteins in the canonical Wnt signalling pathway. Similarly, elevated levels of klotho expression in vivo prevent the exercise-induced increase in myogenin-expressing cells and reduce exercise-induced activation of the Wnt pathway. These findings demonstrate a new mechanism through which the responses of muscle to the mechanical environment are regulated.
ABSTRACT
Muscle growth is influenced by changes in the mechanical environment that affect the expression of genes that regulate myogenesis. We tested whether the hormone Klotho could influence the response of muscle to mechanical loading. Applying mechanical loads to myoblasts in vitro increased RNA encoding transcription factors that are expressed in activated myoblasts (Myod) and in myogenic cells that have initiated terminal differentiation (Myog). However, application of Klotho to myoblasts prevented the loading-induced activation of Myog without affecting loading-induced activation of Myod. This indicates that elevated Klotho inhibits mechanically-induced differentiation of myogenic cells. Elevated Klotho also reduced the transcription of genes encoding proteins involved in the canonical Wnt pathway or their target genes (Wnt9a, Wnt10a, Ccnd1). Because the canonical Wnt pathway promotes differentiation of myogenic cells, these findings indicate that Klotho inhibits the differentiation of myogenic cells experiencing mechanical loading. We then tested whether these effects of Klotho occurred in muscles of mice experiencing high-intensity interval training (HIIT) by comparing wild-type mice and klotho transgenic mice. The expression of a klotho transgene combined with HIIT synergized to tremendously elevate numbers of Pax7 satellite cells and activated MyoD cells. However, transgene expression prevented the increase in myogenin cells caused by HIIT in wild-type mice. Furthermore, transgene expression diminished the HIIT-induced activation of the canonical Wnt pathway in Pax7 satellite cells. Collectively, these findings show that Klotho inhibits loading- or exercise-induced activation of muscle differentiation and indicate a new mechanism through which the responses of muscle to the mechanical environment are regulated.
Topics: Animals; Mice; Cell Differentiation; Hormones; Muscle Development; Muscle, Skeletal; Muscles; MyoD Protein; Myogenin; Satellite Cells, Skeletal Muscle
PubMed: 37864311
DOI: 10.1113/EP091263 -
Journal of Hematopathology Jun 2023An 18-year-old female presented with a 4.5 cm abdominal mass. Biopsy showed sheet-like growth of large tumor cells with round to oval nuclei, 1-2 nucleoli, and abundant...
An 18-year-old female presented with a 4.5 cm abdominal mass. Biopsy showed sheet-like growth of large tumor cells with round to oval nuclei, 1-2 nucleoli, and abundant cytoplasm. Immunohistochemistry showed strong, uniform CD30 staining and cytoplasmic ALK staining. B-cell markers (CD20, CD79a, PAX5, kappa/lambda) and T-cell markers (CD2, CD3, CD4, CD5, CD43, granzyme B, T-cell receptor-β) were negative. Other hematopoietic markers (CD45, CD34, CD117, CD56, CD163, EBV) were negative, but CD138 was positive. Non-hematopoietic markers showed desmin positivity and negativity for S100, melan A, HBM45, PAX8, PAX2, WT1, MYO-D1, myogenin, pancytokeratin, and CAM5.2. Sequencing identified fusion. A diagnosis of epithelioid inflammatory myofibroblastic sarcoma (EIMS) was made. EIMS is a rare, aggressive form of inflammatory myofibroblastic tumor typically presenting in children and young adults. The tumor comprises large epithelioid cells that express ALK and often CD30. ALK-positive ALCL has a similar age range and also is a large-cell tumor expressing CD30 and ALK. Other ALK-positive neoplasms (e.g., carcinomas, ALK-positive large B-cell lymphoma, ALK-positive histiocytosis) typically lack CD30 and have distinct clinicopathologic features that aid diagnosis. Hematopathologists need to distinguish EIMS from ALK-positive ALCL, which frequently shows loss of pan-T-cell antigens. Careful morphologic evaluation for the hallmark cells of ALCL and comprehensive phenotyping are critical to avoid this diagnostic pitfall. If known, the rearrangement partner gene may also provide diagnostic clues; for example and occur in EIMS but not ALCL.
PubMed: 37398940
DOI: 10.1007/s12308-023-00537-8