The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA875101 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21354900_1.fastq.gz | Fastqsanger.gz | |||
| SRR21354900_2.fastq.gz | Fastqsanger.gz | |||
| SRR21354901_1.fastq.gz | Fastqsanger.gz | |||
| SRR21354901_2.fastq.gz | Fastqsanger.gz | |||
| SRR21354902_1.fastq.gz | Fastqsanger.gz |
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Project description:Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling that is expressed at all neuromuscular junctions and is also present extrasynaptically in the slow soleus muscle. To investigate the role of the MuSK-BMP pathway in vivo we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice myofibers are smaller in the slow soleus, but not in the fast TA. Here we use bulk RNA-seq to perform transcriptomic analysis of slow and fast mouse muscle. RNAseq analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1 pathway components. Moreover, Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including the IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
2024-01-10 | GSE212352 | GEO
Project description:Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
| S-EPMC10763067 | biostudies-literature
Project description:Bone morphogenic proteins (BMPs) function in virtually all tissues with cell-type specific outcomes. Since there are a relatively small number of BMP receptors this exquisite signaling specificity requires additional molecules to regulate the output of this pathway. We demonstrated that the receptor tyrosine kinase MuSK that is selectively expressed in muscle and plays a critical role in synapse formation and maintenance binds to BMP4 and related BMPs. Since BMPs regulate the transcription of a set of genes, we performed microarrays for wild-type and MuSK null muscle cells to test if MuSK regulates BMP responses in muscle cells. We shought to determine if MuSK regulates BMP responses in muscle cells and if the cell context made any difference in MuSK regulation of BMP pathway. To test this, expression profiles of untreated vs. BMP4-treated undifferentiated myoblast and differentiated myotube cultures were generated for both wild-type and MuSK-null genotypes. All conditions were done in triplicates. In total 24 arrays were analyzed.
2015-08-03 | E-GEOD-59567 | biostudies-arrayexpress
Project description:Bone morphogenic proteins (BMPs) function in virtually all tissues with cell-type specific outcomes. Since there are a relatively small number of BMP receptors this exquisite signaling specificity requires additional molecules to regulate the output of this pathway. We demonstrated that the receptor tyrosine kinase MuSK that is selectively expressed in muscle and plays a critical role in synapse formation and maintenance binds to BMP4 and related BMPs. Since BMPs regulate the transcription of a set of genes, we performed microarrays for wild-type and MuSK null muscle cells to test if MuSK regulates BMP responses in muscle cells.
2015-08-03 | GSE59567 | GEO
Project description:The Chinese forest musk deer (FMD; Moschus berezovskii) is an endangered artiodactyl mammal. Musk secreted by the musk gland of male FMD has extremely high economic and medicinal value. At present, little is known about the development of musk glands and the molecular mechanism of musk secretion. In the present research, using snRNA-seq and snATAC-seq association analysis performed on musk glands of forest musk deer, coupled with several bioinformatics analyses, the dynamic transcriptional cell atlas of musk gland development was revealed and the genes and transcription factors affecting musk secretion were determined. Based on uniform manifold approximation and projection (UMAP) analysis, we identified 12 cell types from musk glands, including two different acinar cells (clusters 0 and 10). In addition, the expression of core target genes and core transcription factors was verified by fluorescence in situ hybridization and immunohistochemistry. Combined with weighted gene co-expression network analysis (WGCNA), we obtained a deeper biological understanding of the relationship between core transcription factors, differentially expressed genes and musk secretion related pathways. This study lays a foundation for improving musk yield and meeting market demand. In the meantime, it also contributes to reducing the hunting and poaching of wild forest musk deer, protecting forest musk deer resources and maintaining ecological balance.
2023-08-31 | GSE182087 | GEO
Project description:Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that mouse Fibcd1 is an evolutionary-conserved myokine that preserves myofiber size via ERK signaling. Local administration of recombinant Fibcd1 (rFibcd1) ameliorates cachexia-induced myofiber atrophy in the diaphragm of mice bearing patient-derived melanoma xenografts and LLC carcinomas. Moreover, rFibcd1 impedes cachexia-associated transcriptional changes in the diaphragm. Fibcd1-induced signaling appears to be muscle selective because rFibcd1 increases ERK activity in myotubes but not in several cancer cell lines tested. We propose that rFibcd1 may help reinstate myofiber size in the diaphragm of patients with cancer cachexia.
2022-02-28 | GSE156815 | GEO
Project description:Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that mouse Fibcd1 is an evolutionary-conserved myokine that preserves myofiber size via ERK signaling. Local administration of recombinant Fibcd1 (rFibcd1) ameliorates cachexia-induced myofiber atrophy in the diaphragm of mice bearing patient-derived melanoma xenografts and LLC carcinomas. Moreover, rFibcd1 impedes cachexia-associated transcriptional changes in the diaphragm. Fibcd1-induced signaling appears to be muscle selective because rFibcd1 increases ERK activity in myotubes but not in several cancer cell lines tested. We propose that rFibcd1 may help reinstate myofiber size in the diaphragm of patients with cancer cachexia.
2022-02-28 | GSE158581 | GEO
Project description:Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that mouse Fibcd1 is an evolutionary-conserved myokine that preserves myofiber size via ERK signaling. Local administration of recombinant Fibcd1 (rFibcd1) ameliorates cachexia-induced myofiber atrophy in the diaphragm of mice bearing patient-derived melanoma xenografts and LLC carcinomas. Moreover, rFibcd1 impedes cachexia-associated transcriptional changes in the diaphragm. Fibcd1-induced signaling appears to be muscle selective because rFibcd1 increases ERK activity in myotubes but not in several cancer cell lines tested. We propose that rFibcd1 may help reinstate myofiber size in the diaphragm of patients with cancer cachexia.
2022-02-28 | GSE183833 | GEO
Project description:Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity
| PRJNA747287 | ENA
Project description:The development of the neuromuscular synapse depends on signaling processes which involve protein phosphorylation as a crucial regulatory event. The receptor tyrosine kinase MuSK is the key signaling molecule at the neuromuscular synapse whose activity is required for the formation of a mature and functional neuromuscular synapse. However, the signaling cascade downstream of MuSK and the regulation of the different components is still poorly understood. Here we present data from a quantitative phosphoproteomics approach to study MuSK-dependent processes. Muscle cells were stimulated with the heparansulfate proteoglycan agrin, which activates MuSK and downstream signaling events. To get an insight into the signaling dynamics we used three different time points (unstimulated, 15 min, 60 min and 4 hrs).
2014-06-05 | PXD000558 | Pride