scholarly journals Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype

2019 ◽  
Author(s):  
Hannah E. Wilson ◽  
David A. Stanton ◽  
Cortney Montgomery ◽  
Aniello M. Infante ◽  
Matthew Taylor ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Molecular Subtype ◽  
Clinical History ◽  
Muscle Gene Expression ◽  
Treatment History ◽  
Muscle Gene

ABSTRACTIncreased susceptibility to fatigue is a negative predictor of survival commonly experienced by women with breast cancer. Here, we sought to identify molecular changes induced in human skeletal muscle by BC regardless of treatment history or tumor molecular subtype using RNA-sequencing and proteomic analyses. Mitochondrial dysfunction was apparent across all molecular subtypes, with the greatest degree of transcriptomic changes occurring in women with HER2/neu-overexpressing tumors, though muscle from patients of all subtypes exhibited similar pathway-level dysregulation. Interestingly, we found no relationship between anti-cancer treatments and muscle gene expression, suggesting that fatigue is a product of BC per se rather than clinical history. In vitro and in vivo experimentation confirmed the ability of BC cells to alter mitochondrial function and ATP content in muscle. These data suggest that interventions supporting muscle in the presence of BC-induced mitochondrial dysfunction may alleviate fatigue and improve the lives of women with BC.

scholarly journals Myogenin is required for assembly of the transcription machinery on muscle genes during skeletal muscle differentiation

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245618
Author(s):  
Abhinav Adhikari ◽  
William Kim ◽  
Judith Davie
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Gene Activation ◽  
Gene Promoters ◽  
Muscle Gene Expression ◽  
Transcription Machinery ◽  
Muscle Genes ◽  
Muscle Gene

Skeletal muscle gene expression is governed by the myogenic regulatory family (MRF) which includes MyoD (MYOD1) and myogenin (MYOG). MYOD1 and MYOG are known to regulate an overlapping set of muscle genes, but MYOD1 cannot compensate for the absence of MYOG in vivo. In vitro, late muscle genes have been shown to be bound by both factors, but require MYOG for activation. The molecular basis for this requirement was unclear. We show here that MYOG is required for the recruitment of TBP and RNAPII to muscle gene promoters, indicating that MYOG is essential in assembling the transcription machinery. Genes regulated by MYOD1 and MYOG include genes required for muscle fusion, myomaker and myomerger, and we show that myomaker is fully dependent on activation by MYOG. We also sought to determine the role of MYOD1 in MYOG dependent gene activation and unexpectedly found that MYOG is required to maintain Myod1 expression. However, we also found that exogenous MYOD1 was unable to compensate for the loss of Myog and activate muscle gene expression. Thus, our results show that MYOD1 and MYOG act in a feed forward loop to maintain each other’s expression and also show that it is MYOG, and not MYOD1, that is required to load TBP and activate gene expression on late muscle gene promoters bound by both factors.

Stable incorporation of a bacterial gene into adult rat skeletal muscle in vivo

1990 ◽  
Vol 258 (3) ◽  
pp. C578-C581 ◽  
Author(s):  
D. B. Thomason ◽  
F. W. Booth
Keyword(s):  
Skeletal Muscle ◽  
Leukemia Virus ◽  
Rat Skeletal Muscle ◽  
Bacterial Gene ◽  
Muscle Gene Expression ◽  
Adult Rat ◽  
Foreign Genes ◽  
Muscle Gene ◽  
Beta Galactosidase

We have developed a novel technique to incorporate and stably express foreign genes in adult rat skeletal muscle in vivo. Endogeneous satellite cells in skeletal muscle regenerating from bupivacaine damage were infected with an injected retrovirus containing the Escherichia coli beta-galactosidase gene under the promoter control of the Moloney murine leukemia virus long-terminal repeat. Constitutive and stable expression of beta-galactosidase activity was observed in muscle fibers after 6 days and 1 mo of muscle regeneration. Two patterns of expression were observed, diffuse expression within fibers and focal expression associated with the sarcolemma. This technique will allow future experiments with muscle-specific genes and promoters to study the physiological regulation of skeletal muscle gene expression in the intact adult mammal. Furthermore, the technique of stimulating stem cell proliferation to allow retroviral-mediated gene transfer may be generally applicable to other tissues.

scholarly journals Isoform-specific promotion of breast cancer tumorigenicity by TBX3 involves induction of angiogenesis

2019 ◽  
Vol 100 (3) ◽  
pp. 400-413
Author(s):  
Milica Krstic ◽  
Haider M. Hassan ◽  
Bart Kolendowski ◽  
M. Nicole Hague ◽  
Pieter. H. Anborgh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Subtype ◽  
Xenograft Model ◽  
Tumor Formation ◽  
Transcriptional Analysis ◽  
Breast Cancer Cell Lines ◽  
Tumor Vascularity ◽  
Mouse Xenograft Model

Abstract TBX3 is a member of the highly conserved family of T-box transcription factors involved in embryogenesis, organogenesis and tumor progression. While the functional role of TBX3 in tumorigenesis has been widely studied, less is known about the specific functions of the different isoforms (TBX3iso1 and TBX3iso2) which differ in their DNA-binding domain. We therefore sought to investigate the functional consequence of this highly conserved splice event as it relates to TBX3-induced tumorigenesis. By utilizing a nude mouse xenograft model, we have identified differential tumorigenic potential between TBX3 isoforms, with TBX3iso1 overexpression more commonly associated with invasive carcinoma and high tumor vascularity. Transcriptional analysis of signaling pathways altered by TBX3iso1 and TBX3iso2 overexpression revealed significant differences in angiogenesis-related genes. Importantly, osteopontin (OPN), a cancer-associated secreted phosphoprotein, was significantly up-regulated with TBX3iso1 (but not TBX3iso2) overexpression. This pattern was observed across three non/weakly-tumorigenic breast cancer cell lines (21PT, 21NT, and MCF7). Up-regulation of OPN in TBX3iso1 overexpressing cells was associated with induction of hyaluronan synthase 2 (HAS2) expression and increased retention of hyaluronan in pericellular matrices. These transcriptional changes were accompanied by the ability to induce endothelial cell vascular channel formation by conditioned media in vitro, which could be inhibited through addition of an OPN neutralizing antibody. Within the TCGA breast cancer cohort, we identified an 8.1-fold higher TBX3iso1 to TBX3iso2 transcript ratio in tumors relative to control, and this ratio was positively associated with high-tumor grade and an aggressive molecular subtype. Collectively, the described changes involving TBX3iso1-dependent promotion of angiogenesis may thus serve as an adaptive mechanism within breast cancer cells, potentially explaining differences in tumor formation rates between TBX3 isoforms in vivo. This study is the first of its kind to report significant functional differences between the two TBX3 isoforms, both in vitro and in vivo.

Integrin signaling's potential for mediating gene expression in hypertrophying skeletal muscle

2000 ◽  
Vol 88 (1) ◽  
pp. 337-343 ◽  
Author(s):  
James A. Carson ◽  
Lei Wei
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Signaling Pathway ◽  
Mechanical Load ◽  
Integrin Signaling ◽  
Mechanical Forces ◽  
Growth Factor Signaling ◽  
Muscle Gene

Overloaded skeletal muscle undergoes dramatic shifts in gene expression, which alter both the phenotype and mass. Molecular biology techniques employing both in vivo and in vitro hypertrophy models have demonstrated that mechanical forces can alter skeletal muscle gene regulation. This review's purpose is to support integrin-mediated signaling as a candidate for mechanical load-induced hypertrophy. Research quantifying components of the integrin-signaling pathway in overloaded skeletal muscle have been integrated with knowledge regarding integrins role during development and cardiac hypertrophy, with the hope of demonstrating the pathway's importance. The role of integrin signaling as an integrator of mechanical forces and growth factor signaling during hypertrophy is discussed. Specific components of integrin signaling, including focal adhesion kinase and low-molecular-weight GTPase Rho are mentioned as downstream targets of this signaling pathway. There is a need for additional mechanistic studies capable of providing a stronger linkage between integrin-mediated signaling and skeletal muscle hypertrophy; however, there appears to be abundant justification for this type of research.

scholarly journals DLL4 and PDGF-BB regulate migration of human iPSC-derived skeletal myogenic progenitors

2021 ◽  
Author(s):  
Giulia Ferrari ◽  
SungWoo Choi ◽  
Louise Anne Moyle ◽  
Kirsty Mackinlay ◽  
Naira Naouar ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Cell Migration ◽  
Negative Impact ◽  
Muscle Growth ◽  
Differentiation Potential ◽  
Cell Therapies ◽  
Muscle Gene

Muscle satellite stem cells (MuSCs) are responsible for skeletal muscle growth and regeneration. Despite their differentiation potential, human MuSCs have limited in vitro amplification and in vivo migration capacity, limiting their use in cell therapies for diseases affecting multiple skeletal muscle groups such as muscular dystrophies. Several protocols have been established to derive progenitor cells similar to MuSCs from human induced pluripotent stem cells (hiPSCs), in order to establish a source of myogenic cells with controllable proliferation and differentiation capacity. However, currently available hiPSC myogenic derivatives also suffer from limitations of cell migration, ultimately delaying their clinical translation. Here we provide evidence that activation of NOTCH and PDGF pathways with DLL4 and PDGF-BB improves migration of hiPSC-derived myogenic progenitors in vitro. Transcriptomic and functional analyses demonstrate that this property is conserved across species and multiple hiPSC lines, including genetically-corrected hiPSC derivatives from a patient with Duchenne muscular dystrophy. DLL4 and PDGF-BB treatment had no negative impact on cell proliferation; cells maintained their myogenic memory, with differentiation fully rescued by NOTCH inhibition. RNAseq analysis indicate that pathways involved in cell migration are modulated in treated myogenic progenitors, consistent with results from functional profiling of cell motility at single cell resolution. Notably, treated cells also showed enhanced trans-endothelial migration in transwell assays. Enhancing extravasation is a key translational milestone for intravascular delivery of hiPSC myogenic derivatives: our study establishes the foundations of a transgene-free, developmentally inspired strategy to achieve this goal, moving hiPSCs one step closer to future muscle gene and cell therapies.

Epigenetic effects induced by the ectopic expression of Pax7 in 3T3-L1

2021 ◽  
Author(s):  
Alaa Elgaabari ◽  
Atsuko Miyawaki-Kuwakado ◽  
Kosuke Tomimatsu ◽  
Qianmei Wu ◽  
Kosuke Tokunaga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Ectopic Expression ◽  
Histone Mark ◽  
Differentiation Potential ◽  
Muscle Gene Expression ◽  
Repressive Histone Mark ◽  
Myogenic Factor ◽  
Muscle Gene

Abstract Although skeletal muscle cells and adipocytes are derived from the same mesoderm, they do not transdifferentiate in vivo and are strictly distinct at the level of gene expression. To elucidate some of the regulatory mechanisms underlying this strict distinction, Pax7, a myogenic factor, was ectopically expressed in 3T3-L1 adipose progenitor cells to perturb their adipocyte differentiation potential. Transcriptome analysis showed that ectopic expression of Pax7 repressed the expression of some adipocyte genes and induced expression of some skeletal muscle cell genes. We next profiled the epigenomic state altered by Pax7 expression using H3K27ac, an activating histone mark, and H3K27me3, a repressive histone mark, as indicators. Our results show that ectopic expression of Pax7 did not result in the formation of H3K27ac at loci of skeletal muscle-related genes, but instead resulted in the formation of H3K27me3 at adipocyte-related gene loci. These findings suggest that the primary function of ectopic Pax7 expression is the formation of H3K27me3, and muscle gene expression results from secondary regulation.

Regulation of IκB kinase and NF-κB in contracting adult rat skeletal muscle

2005 ◽  
Vol 289 (4) ◽  
pp. C794-C801 ◽  
Author(s):  
Richard C. Ho ◽  
Michael F. Hirshman ◽  
Yangfeng Li ◽  
Dongsheng Cai ◽  
Jocelyn R. Farmer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Time Course ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Muscle Gene Expression ◽  
Iκb Kinase ◽  
Gastrocnemius Muscles

Nuclear factor-κB (NF-κB) is a transcription factor with important roles in regulating innate immune and inflammatory responses. NF-κB is activated through the phosphorylation of its inhibitor, IκB, by the IκB kinase (IKK) complex. Physical exercise elicits changes in skeletal muscle gene expression, yet signaling cascades and transcription factors involved remain largely unknown. To determine whether NF-κB signaling is regulated by exercise in vivo, rats were run on a motorized treadmill for 5–60 min. Exercise resulted in up to twofold increases in IKKα/β phosphorylation in the soleus and red gastrocnemius muscles throughout the time course studied. In red gastrocnemius muscles, NF-κB activity increased 50% 1–3 h after 60 min of treadmill exercise, returning to baseline by 5 h. Contraction of isolated extensor digitorum longus muscles in vitro increased IKKα/β phosphorylation sevenfold and this was accompanied by a parallel increase in IκBα phosphorylation. Additional kinases that are activated by exercise include p38, extracellular-signal regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK). Inhibitors of p38 (SB-203580) and ERK (U-0126) blunted contraction-mediated IKK phosphorylation by 39 ± 4% ( P = 0.06) and 35 ± 10% ( P = 0.09), respectively, and in combination by 76 ± 5% ( P < 0.05), suggesting that these kinases might influence the activation of IKK and NF-κB during exercise. In contrast, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, an activator of AMPK, had no effect on either IKK or NF-κB activity. In conclusion, acute submaximal exercise transiently stimulates NF-κB signaling in skeletal muscle. This activation is a local event because it can occur in the absence of exercise-derived systemic factors.

scholarly journals Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Hannah E. Wilson ◽  
David A. Stanton ◽  
Cortney Montgomery ◽  
Aniello M. Infante ◽  
Matthew Taylor ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Skeletal Muscle ◽  
Molecular Subtype ◽  
Treatment History
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