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Annotating the secretome of mature primary human muscle cells

ABSTRACT: The Skeletal muscle is a metabolic active tissue that secretes various proteins. These so called myokines act auto-, para- and endocrine affecting muscle physiology and exert systemic effects on other tissues and organs. Myokines are also described to play a crucial role in the pathophysiology of metabolic diseases. Combining three different mass spectrometry based non-targeted and one antibody based targeted approach we investigated the secretome of differentiated primary human skeletal muscle cells derived from adult donors. A total of 548 non-redundant proteins were detected by combined proteomic profiling. Expression was confirmed on mRNA level for 501. Stringent consecutive filtering recruiting several database, i.e. SignalP, SecretomeP and ER_retention signals, the computational analysis assigned 306 as secretory proteins including 33 potentially novel myokines. This comprehensive profiling study of the human skeletal muscle secretome expands our knowledge of the composition of the human myokinome and further highlights the pivotal role of myokines in the regulation of multiple biological processes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45473 | GEO | 2013/12/03

SECONDARY ACCESSION(S): PRJNA194109

REPOSITORIES: GEO

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Annotating the secretome of mature primary human muscle cells

Project description:The Skeletal muscle is a metabolic active tissue that secretes various proteins. These so called myokines act auto-, para- and endocrine affecting muscle physiology and exert systemic effects on other tissues and organs. Myokines are also described to play a crucial role in the pathophysiology of metabolic diseases. Combining three different mass spectrometry based non-targeted and one antibody based targeted approach we investigated the secretome of differentiated primary human skeletal muscle cells derived from adult donors. A total of 548 non-redundant proteins were detected by combined proteomic profiling. Expression was confirmed on mRNA level for 501. Stringent consecutive filtering recruiting several database, i.e. SignalP, SecretomeP and ER_retention signals, the computational analysis assigned 306 as secretory proteins including 33 potentially novel myokines. This comprehensive profiling study of the human skeletal muscle secretome expands our knowledge of the composition of the human myokinome and further highlights the pivotal role of myokines in the regulation of multiple biological processes. We performed gene expression microarray analysis of primary human myotubes derived from twelve healthy individuals

2013-12-03 | E-GEOD-45473 | biostudies-arrayexpress

Cytokines dominate the secretome of primary human myotubes in an in vitro exercise model

Project description:Muscle contraction during exercise is the major stimulus for the release of peptides and proteins (myokines) that are supposed to take part in the benefical adaptation to exercise. We hypothesize that application of an in vitro exercise stimulus as electric pulse stimulation (EPS) to human myotubes enables the investigation of the human muscle secretome in a clearly defined model. We applied EPS for 24 h to primary human myotubes and studied the whole genome-wide transcriptional response and as well as the release of candidate myokines. We observed 183 differentially regulated transcripts with fold-changes > 1.3. The transcriptional response resembles several properties of the in vivo situation in the skeletal muscle after endurance exercise, namely significant enrichment of pathways associated with interleukin and chemokine signaling, lipid metabolism, and anti-oxidant defense; notably without increased release of creatin kinase. Multiplex immunoassays verified the translation of the transcriptional response of several myokines into high secretion levels (IL6, IL8, CXCL1, LIF, CSF3, IL1B, TNF) and identified an increased secretion of additional cytokines (IL2, IL4, IL13, IL17A). Inhibitor studies and immunoblotting revealed the participation of ERK1/2 and AMPK dependent pathways in the upregulation of myokines. To conclude our data highlight the importance of skeletal muscle cells per se as endocrine cells. This in vitro exercise model is not only suitable to identify known and novel exercise-regulated myokines but it might be applied to primary human myotubes obtained from different muscle biopsy donors to study molecular mechanisms of the individual response to exercise. We performed gene expression microarray analysis of myotubes in vitro stimulated by EPS and control myotubes

2013-10-09 | E-GEOD-44051 | biostudies-arrayexpress

Cytokines dominate the secretome of primary human myotubes in an in vitro exercise model

2013-10-09 | GSE44051 | GEO

RNA-Seq of Myf6-knockout versus Wild-type satellite cells

Project description:In metazoans, skeletal muscle evolved to contract and produce force. Recent experimental evidence, however, suggests that skeletal muscle has also acquired endocrine functions and produces a vast array of muscle-derived cytokines and growth factors, collectively called myokines. The mechanisms that regulate myokine production and their effect on the resident stem cell population inskeletal muscle remain unknown. Here, we report that in adult skeletal muscle, Myf6/MRF4 is a major regulator of myokine expression. Genetic deletion of Myf6 in skeletal muscle leads to reduction of the muscle stem cell (MuSCs) pool in adult mice in a myokine-dependent manner but, surprisingly, does not disrupt muscle differentiation. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 is a direct regulator of many myokines and muscle-secreted proteins, including ligands for canonical signaling pathways such as EGFR and VEGFR. Consequently, in Myf6-deficient animals,MuSCs increasingly break quiescence, but can nevertheless undergo differentiation. Lastly, we show that Myf6 and its gene network rapidly respondto aerobic and anaerobic exercise. Together, these findings indicate that control of myokine signaling by Myf6 is critical to maintain muscle stem cell pool and skeletal muscle function via myokine signaling.

2020-10-02 | GSE133505 | GEO

Myf6/MRF4 Mediated Myokine Signaling is Required for the Maintenance of the Adult Skeletal Muscle Stem Cell Pool

Project description:In metazoans, skeletal muscle evolved to contract and to produce force. Recent experimental evidence suggests, however, that skeletal muscle has also acquired endocrine functions and produces a vast array of myokines, but how myokine production is regulated and how they affect the resident stem cell population of the skeletal muscle is unknown. Here, we show that in adult skeletal muscle, Myf6/MRF4 is a major regulator of myokine expression. Genetic deletion of Myf6 in skeletal muscles leads to exhaustion of the muscle stem cell (MuSCs) pool in adult mice in a myokine-dependent manner but, surprisingly, does not disrupt muscle differentiation. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 is essential for the transcriptional activation of many myokines and muscle-secreted proteins, including ligands for canonical signaling pathways such as EGFR, VEGFR and STAT3. Consequently, MuSCs from Myf6 knockout animals show impaired activation of those signaling pathways and exhibit impaired quiescence, defective self-renewal, but nevertheless undergo differentiation. Lastly, we show that induction of myokine expression during aerobic and anaerobic exercise closely correlates with Myf6 expression. Together, these findings indicate that control of myokine signaling by Myf6 is critical to maintain muscle stem cell pool in adult skeletal muscle.

2020-09-18 | GSE123836 | GEO

Skeletal muscle TFEB overexpression transcriptionally remodels the mouse hippocampal landscape throughout lifespan in a sex-dependent manner [RNA-seq]

Project description:Skeletal muscle has recently arisen as a novel regulator of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis- and metabolism-modifying functions in targeted tissues, including the CNS. We generated a novel transgenic mouse that has overexpression of Transcription Factor E-B (TFEB), a master regulator of proteostasis and lysosomal function, in skeletal muscle. We discovered that the resulting changes in muscle function promotes transcriptional remodeling of the aging CNS, as well as preserves cognition and memory in aging mice. Our results implicate the maintenance of autophagic skeletal muscle signaling throughout aging to the direct regulation of the CNS metabolism and function, and suggest that skeletal muscle originating factors may act as novel therapeutic targets against age-associated neurodegenerative diseases.

2024-02-14 | GSE242361 | GEO

RNA sequencing of TA muscle in miR-501KO mice and control littermates at day 6 of CTX-induced muscle regeneration

Project description:Adult muscle stem cells show a high transcriptional and clonal heterogeneity during ageing. Whether microRNAs contribute to this diversity is not known. Here we use global and tissue-specific genetic deletion of microRNA (miR)-501 that is highly enriched in activated myogenic progenitor cells 3 to address this question. Deletion of miR-501 reduced myofiber size and resilience of muscle fibers to injury and exercise in adult skeletal muscle. miR-501 elicits this effect by changing sarcomeric gene expression in newly built myofibers in vivo.

2023-03-16 | GSE199111 | GEO

Insulin and 5-aminoimidazole-4-carboxamide Ribonucleotide (AICAR) Differentially Regulate the Skeletal Muscle Cell Secretome

Project description:Skeletal muscle is a major contributor to whole-body glucose homeostasis and is an important endocrine organ. To date, few studies have undertaken the large-scale identification of skeletal muscle-derived secreted proteins (myokines), particularly in response to stimuli that activate pathways governing energy metabolism in health and disease. Whereas the AMP-activated protein kinase (AMPK) and insulin-signaling pathways have received notable attention for their ability to independently regulate skeletal muscle substrate metabolism, little work has examined their ability to re-pattern the secretome. The present study coupled the use of high-resolution MS-based proteomics and bioinformatics analysis of conditioned media derived from 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR – an AMPK activator)- and insulin-treated differentiated C2C12 myotubes. We quantified 858 secreted proteins, including cytokines and growth factors such as fibroblast growth factor-21 (Fgf21). We identified 377 and 118 proteins that were significantly altered by Insulin and AICAR treatment, respectively. Notably, the family of insulin growth factor binding-proteins (Igfbp) was differentially regulated by each treatment. Insulin- but not AICAR-induced conditioned media increased the mitochondrial respiratory capacity of myotubes, potentially via secreted factors. These findings may serve as an important resource to elucidate secondary metabolic effects of insulin and AICAR stimulation in skeletal muscle.

2021-09-15 | PXD025687 | Pride

Mining the secretome of C2C12 muscle cells

Project description:Secretome analysis faces several challenges, including detection of low abundant proteins and the discrimination of bona fide secreted proteins from false-positive identifications stemming from cell leakage or serum. Here, we developed a two-step secretomics approach and applied it for the analysis of secreted proteins of C2C12 skeletal muscle cells as the skeletal muscle has been identified as an important endocrine organ secreting myokines as active signaling molecules. First, we compared culture supernatants and corresponding cell lysates by high-resolution MS-based proteomics and label-free quantification. We found 672 protein groups as candidate secreted proteins, as they showed a higher abundance in the secretome. By Brefeldin A mediated blocking of classical secretory processes, we estimate a sensitivity of > 80% for the detection of classical secreted proteins by our experimental approach. In the second step, peptide level information was integrated with UniProt based protein information by the bioinformatics tool “lysate and secretome peptide feature plotter” (LSPFP) to detect proteolytic protein processing events which might occur during secretion e.g. As a proof on concept, we identified truncations of the cytoplasmic part of the protein Plexin-B2. Our workflow provides an efficient combination of experimental workflow and data analysis to identify putative secreted and proteolytic processed proteins.

2018-01-24 | PXD007527 | Pride

The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling

Project description:Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we find that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX, which promotes and is necessary for myoblast fusion. MLX promotes myogenesis not via an adjustment of glucose metabolism but rather by inducing the expression of several myokines, including insulin like-growth factor-2 (IGF2), whereas RNAi and dominant-negative MLX reduce IGF2 expression and block myogenesis. This phenotype is rescued by conditioned media from control muscle cells and by recombinant IGF2, which activates the myogenic kinase Akt. Importantly, MLX null mice display decreased IGF2 induction and diminished muscle regeneration in response to injury, indicating that the myogenic function of MLX is conserved in vivo. Thus, glucose is a signaling molecule that regulates myogenesis and muscle regeneration via MLX/IGF2/Akt signaling.â??The data pproided are histome H4 acetlation data for MLX DN and MLX wt samples; 3 MLX DN H4 Ac Chip seq samples , 3 Inputs, 3 MLX WT H4 Ac samples and 3 WT inputs

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