Tumor-derived cytokines impair myogenesis and alter the skeletal muscle immune microenvironment.
Ontology highlight
ABSTRACT:
SUBMITTER: Hogan KA
PROVIDER: S-EPMC5916328 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
Publications
Tumor-derived cytokines impair myogenesis and alter the skeletal muscle immune microenvironment.
Hogan Kelly A KA Cho Dong Seong DS Arneson Paige C PC Samani Adrienne A Palines Patrick P Yang Yanan Y Doles Jason D JD
Cytokine 20171117
Muscle wasting is a decline in skeletal muscle mass and function that is associated with aging, obesity, and a spectrum of pathologies including cancer. Cancer-associated wasting not only reduces quality of life, but also directly impacts cancer mortality, chemotherapeutic efficacy, and surgical outcomes. There is an incomplete understanding of the role of tumor-derived factors in muscle wasting and sparse knowledge of how these factors impact in vivo muscle regeneration. Here, we identify sever ...[more]
Similar Datasets
Project description:Dermatopontin (DPT) is an extensively distributed non-collagenous component of the extracellular matrix predominantly found in the dermis of the skin, and consequently expressed in several tissues. In this study, we explored the role of DPT in myogenesis and perceived that it enhances the cell adhesion, reduces the cell proliferation and promotes the myoblast differentiation in C2C12 cells. Our results reveal an inhibitory effect with fibronectin (FN) in myoblast differentiation. We also observed that DPT and fibromodulin (FMOD) regulate positively to each other and promote myogenic differentiation. We further predicted the 3D structure of DPT, which is as yet unknown, and validated it using state-of-the-art in silico tools. Furthermore, we explored the in-silico protein-protein interaction between DPT-FMOD, DPT-FN, and FMOD-FN, and perceived that the interaction between FMOD-FN is more robust than DPT-FMOD and DPT-FN. Taken together, our findings have determined the role of DPT at different stages of the myogenic process.
| S-EPMC6523808 | biostudies-literature
Project description:The chemokine-like receptor-1 (CMKLR1) is a G protein-coupled receptor that is activated by chemerin, a secreted plasma leukocyte attractant and adipokine. Previous studies identified that CMKLR1 is expressed in skeletal muscle in a stage-specific fashion during embryogenesis and in adult mice; however, its function in skeletal muscle remains unclear. Based on the established function of CMKLR1 in cell migration and differentiation, we investigated the hypothesis that CMKLR1 regulates the differentiation of myoblasts into myotubes. In C(2)C(12) mouse myoblasts, CMKLR1 expression increased threefold with differentiation into multinucleated myotubes. Decreasing CMKLR1 expression by adenoviral-delivered small-hairpin RNA (shRNA) impaired the differentiation of C(2)C(12) myoblasts into mature myotubes and reduced the mRNA expression of myogenic regulatory factors myogenin and MyoD while increasing Myf5 and Mrf4. At embryonic day 12.5 (E12.5), CMKLR1 knockout (CMKLR1(-/-)) mice appeared developmentally delayed and displayed significantly lower wet weights and a considerably diminished myotomal component of somites as revealed by immunolocalization of myosin heavy chain protein compared with wild-type (CMKLR1(+/+)) mouse embryos. These changes were associated with increased Myf5 and decreased MyoD protein expression in the somites of E12.5 CMKLR1(-/-) mouse embryos. Adult male CMKLR1(-/-) mice had significantly reduced bone-free lean mass and weighed less than the CMKLR1(+/+) mice. We conclude that CMKLR1 is essential for myogenic differentiation of C(2)C(12) cells in vitro, and the CMKLR1 null mice have a subtle skeletal muscle deficit beginning from embryonic life that persists during postnatal life.
| S-EPMC3378017 | biostudies-literature
Project description:Initiation and progression of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially with regard to immune cell prevalence and presence of mediators of immune function. To better understand the consequences of liver disease on tumor growth and the interplay with its microenvironment, we utilized two standard methods of fibrosis induction and orthotopic implantation of tumors into the inflamed and fibrotic liver to mimic the liver condition in human HCC patients. Compared to non-diseased controls, tumor growth was significantly enhanced under fibrotic conditions. The immune cells that infiltrated the tumors were also drastically different, with decreased numbers of natural killer cells but greatly increased numbers of immune-suppressive CD11b+ Gr1hi myeloid cells in both models of fibrosis. In addition, there were model-specific differences: Increased numbers of CD11b+ myeloid cells and CD4+ CD25+ T cells were found in tumors in the bile duct ligation model but not in the carbon tetrachloride model. Induction of fibrosis altered the cytokine production of implanted tumor cells, which could have farreaching consequences on the immune infiltrate and its functionality. Taken together, this work demonstrates that the combination of fibrosis induction with orthotopic tumor implantation results in a markedly different tumor microenvironment and tumor growth kinetics, emphasizing the necessity for more accurate modeling of HCC progression in mice, which takes into account the drastic changes in the tissue caused by chronic liver disease.
| S-EPMC4445464 | biostudies-literature
Project description:Progressive weight loss combined with skeletal muscle atrophy, termed cachexia, is a common comorbidity associated with cancer that results in adverse consequences for the patient related to decreased chemotherapy responsiveness and increased mortality. Cachexia's complexity has provided a barrier for developing successful therapies to prevent or treat the condition, since a large number of systemic disruptions that can regulate muscle mass are often present. Furthermore, considerable effort has focused on investigating how tumor derived factors and inflammatory mediators directly signal skeletal muscle to disrupt protein turnover regulation. Currently, there is developing appreciation for understanding how cancer alters skeletal muscle's complex microenvironment and the tightly regulated interactions between multiple cell types. Skeletal muscle microenvironment interactions have established functions in muscle response to regeneration from injury, growth, aging, overload-induced hypertrophy, and exercise. This review explores the growing body of evidence for immune cell modulation of the skeletal muscle microenvironment during cancer-induced muscle wasting. Emphasis is placed on the regulatory network that integrates physiological responses between immune cells with other muscle cell types including satellite cells, fibroblast cells, and endothelial cells to regulate myofiber size and plasticity. The overall goal of this review is to provide an understanding of how different cell types that constitute the muscle microenvironment and their signaling mediators contribute to cancer and chemotherapy-induced muscle wasting.
| S-EPMC7489038 | biostudies-literature
Project description:Characterized by their slow adhering property, skeletal muscle myogenic progenitor cells (MPCs) have been widely utilized in skeletal muscle tissue engineering for muscle regeneration, but with limited efficacy. Skeletal muscle regeneration is regulated by various cell types, including a large number of rapidly adhering cells (RACs) where their functions and mechanisms are still unclear. In this study, we explored the function of RACs by co-culturing them with MPCs in a biomimetic skeletal muscle organoid system. Results showed that RACs promoted the myogenic potential of MPCs in the organoid. Single-cell RNA-Seq was also performed, classifying RACs into 7 cell subtypes, including one newly described cell subtype: teno-muscular cells (TMCs). Connectivity map of RACs and MPCs subpopulations revealed potential growth factors (VEGFA and HBEGF) and extracellular matrix (ECM) proteins involvement in the promotion of myogenesis of MPCs during muscle organoid formation. Finally, trans-well experiments and small molecular inhibitors blocking experiments confirmed the role of RACs in the promotion of myogenic differentiation of MPCs. The RACs reported here revealed complex cell diversity and connectivity with MPCs in the biomimetic skeletal muscle organoid system, which not only offers an attractive alternative for disease modeling and in vitro drug screening but also provides clues for in vivo muscle regeneration.
| S-EPMC6546706 | biostudies-literature
Project description:Myotonic dystrophy type 1 (DM1) and 2 (DM2) are autosomal dominant degenerative neuromuscular disorders characterized by progressive skeletal muscle weakness, atrophy, and myotonia with progeroid features. Although both DM1 and DM2 are characterized by skeletal muscle dysfunction and also share other clinical features, the diseases differ in the muscle groups that are affected. In DM1, distal muscles are mainly affected, whereas in DM2 problems are mostly found in proximal muscles. In addition, manifestation in DM1 is generally more severe, with possible congenital or childhood-onset of disease and prominent CNS involvement. DM1 and DM2 are caused by expansion of (CTG•CAG)n and (CCTG•CAGG)n repeats in the 3' non-coding region of DMPK and in intron 1 of CNBP, respectively, and in overlapping antisense genes. This critical review will focus on the pleiotropic problems that occur during development, growth, regeneration, and aging of skeletal muscle in patients who inherited these expansions. The current best-accepted idea is that most muscle symptoms can be explained by pathomechanistic effects of repeat expansion on RNA-mediated pathways. However, aberrations in DNA replication and transcription of the DM loci or in protein translation and proteome homeostasis could also affect the control of proliferation and differentiation of muscle progenitor cells or the maintenance and physiological integrity of muscle fibers during a patient's lifetime. Here, we will discuss these molecular and cellular processes and summarize current knowledge about the role of embryonic and adult muscle-resident stem cells in growth, homeostasis, regeneration, and premature aging of healthy and diseased muscle tissue. Of particular interest is that also progenitor cells from extramuscular sources, such as pericytes and mesoangioblasts, can participate in myogenic differentiation. We will examine the potential of all these types of cells in the application of regenerative medicine for muscular dystrophies and evaluate new possibilities for their use in future therapy of DM.
| S-EPMC5985300 | biostudies-literature
Project description:Skeletal muscle regeneration requires extracellular matrix (ECM) remodeling, including an acute and transient breakdown of collagen that produces gelatin. Although the physiological function of this process is unclear, it has inspired the application of gelatin to injured skeletal muscle for a potential pro-regenerative effect. Here, we investigated a bi-phasic effect of gelatin in skeletal muscle regeneration, mediated by the hormetic effects of reactive oxygen species (ROS). Low-dose gelatin stimulated ROS production from NADPH oxidase 2 (NOX2) and simultaneously upregulated the antioxidant system for cellular defense, reminiscent of the adaptive compensatory process during mild stress. This response triggered the release of the myokine IL-6, which stimulates myogenesis and facilitates muscle regeneration. By contrast, high-dose gelatin stimulated ROS overproduction from NOX2 and the mitochondrial chain complex, and ROS accumulation by suppressing the antioxidant system, triggering the release of TNFα, which inhibits myogenesis and regeneration. Our results have revealed a bi-phasic role of gelatin in regulating skeletal muscle repair mediated by intracellular ROS, the antioxidant system and cytokine (IL-6 and TNFα) signaling.
| S-EPMC8713995 | biostudies-literature
Project description:We previously demonstrated that the expression of intercellular adhesion molecule-1 (ICAM-1) by skeletal muscle cells after muscle overload contributes to ensuing regenerative and hypertrophic processes in skeletal muscle. The objective of the present study is to reveal mechanisms through which skeletal muscle cell expression of ICAM-1 augments regenerative and hypertrophic processes of myogenesis. This was accomplished by genetically engineering C2C12 myoblasts to stably express ICAM-1, and by inhibiting the adhesive and signaling functions of ICAM-1 through the use of a neutralizing antibody or cell penetrating peptide, respectively. Expression of ICAM-1 by cultured skeletal muscle cells augmented myoblast-myoblast adhesion, myotube formation, myonuclear number, myotube alignment, myotube-myotube fusion, and myotube size without influencing the ability of myoblasts to proliferate or differentiate. ICAM-1 augmented myotube formation, myonuclear accretion, and myotube alignment through a mechanism involving adhesion-induced activation of ICAM-1 signaling, as these dependent measures were reduced via antibody and peptide inhibition of ICAM-1. The adhesive and signaling functions of ICAM-1 also facilitated myotube hypertrophy through a mechanism involving myotube-myotube fusion, protein synthesis, and Akt/p70s6k signaling. Our findings demonstrate that ICAM-1 expression by skeletal muscle cells augments myogenesis, and establish a novel mechanism through which the inflammatory response facilitates growth processes in skeletal muscle.
| S-EPMC4323887 | biostudies-literature
Project description:Osteopontin is a multifunctional matricellular protein that is expressed by many cell types. Through cell-matrix and cell-cell interactions the molecule elicits a number of responses from a broad range of target cells via its interaction with integrins and the hyaluronan receptor CD44. In many tissues osteopontin has been found to be involved in important physiological and pathological processes, including tissue repair, inflammation and fibrosis. Post-natal skeletal muscle is a highly differentiated and specialised tissue that retains a remarkable capacity for regeneration following injury. Regeneration of skeletal muscle requires the co-ordinated activity of inflammatory cells that infiltrate injured muscle and are responsible for initiating muscle fibre degeneration and phagocytosis of necrotic tissue, and muscle precursor cells that regenerate the injured muscle fibres. This review focuses on the current evidence that osteopontin plays multiple roles in skeletal muscle, with particular emphasis on its role in regeneration and fibrosis following injury, and in determining the severity of myopathic diseases such as Duchenne muscular dystrophy.
| S-EPMC4063988 | biostudies-literature
Project description:BackgroundMuscle wasting is a debilitating co-morbidity affecting most advanced cancer patients. Alongside enhanced muscle catabolism, defects in muscle repair/regeneration contribute to cancer-associated wasting. Among the factors implicated in suppression of muscle regeneration are cytokines that interfere with myogenic signal transduction pathways. Less understood is how other cancer/wasting-associated cues, such as metabolites, contribute to muscle dysfunction. This study investigates how the metabolite succinate affects myogenesis and muscle regeneration.MethodsWe leveraged an established ectopic metabolite treatment (cell permeable dimethyl-succinate) strategy to evaluate the ability of intracellular succinate elevation to 1) affect myoblast homeostasis (proliferation, apoptosis), 2) disrupt protein dynamics and induce wasting-associated atrophy, and 3) modulate in vitro myogenesis. In vivo succinate supplementation experiments (2% succinate, 1% sucrose vehicle) were used to corroborate and extend in vitro observations. Metabolic profiling and functional metabolic studies were then performed to investigate the impact of succinate elevation on mitochondria function.ResultsWe found that in vitro succinate supplementation elevated intracellular succinate about 2-fold, and did not have an impact on proliferation or apoptosis of C2C12 myoblasts. Elevated succinate had minor effects on protein homeostasis (~25% decrease in protein synthesis assessed by OPP staining), and no significant effect on myotube atrophy. Succinate elevation interfered with in vitro myoblast differentiation, characterized by significant decreases in late markers of myogenesis and fewer nuclei per myosin heavy chain positive structure (assessed by immunofluorescence staining). While mice orally administered succinate did not exhibit changes in overall body composition or whole muscle weights, these mice displayed smaller muscle myofiber diameters (~6% decrease in the mean of non-linear regression curves fit to the histograms of minimum feret diameter distribution), which was exacerbated when muscle regeneration was induced with barium chloride injury. Significant decreases in the mean of non-linear regression curves fit to the histograms of minimum feret diameter distributions were observed 7 days and 28 days post injury. Elevated numbers of myogenin positive cells (3-fold increase) supportive of the differentiation defects observed in vitro were observed 28 days post injury. Metabolic profiling and functional metabolic assessment of myoblasts revealed that succinate elevation caused both widespread metabolic changes and significantly lowered maximal cellular respiration (~35% decrease).ConclusionsThis study broadens the repertoire of wasting-associated factors that can directly modulate muscle progenitor cell function and strengthens the hypothesis that metabolic derangements are significant contributors to impaired muscle regeneration, an important aspect of cancer-associated muscle wasting.
| S-EPMC7470228 | biostudies-literature