Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme originally found in the brain. Our previous work revealed that UCHL1 was also expressed in skeletal muscle and affected myoblast ...differentiation and metabolism. In this study, we further tested the role of UCHL1 in myogenesis and muscle regeneration following muscle ischemia-reperfusion (IR) injury. In the C2C12 myoblast, UCHL1 knockdown upregulated MyoD and myogenin and promoted myotube formation. The skeletal muscle-specific knockout (smKO) of UCHL1 increased muscle fiber sizes in young mice (1 to 2 months old) but not in adult mice (3 months old). In IR-injured hindlimb muscle, UCHL1 was upregulated. UCHL1 smKO ameliorated tissue damage and injury-induced inflammation. UCHL1 smKO also upregulated myogenic factors and promoted functional recovery in IR injury muscle. Moreover, UCHL1 smKO increased Akt and Pink1/Parkin activities. The overall results suggest that skeletal muscle UCHL1 is a negative factor in skeletal muscle development and recovery following IR injury and therefore is a potential therapeutic target to improve muscle regeneration and functional recovery following injuries.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Long noncoding RNAs (lncRNAs) have been reported to play diverse roles in biologic and pathologic processes, including myogenesis. We found that lncRNA AK017368 is highly expressed in skeletal muscle ...cells. Functional analyses showed that overexpression of AK017368 promoted proliferation and restrained differentiation of myoblasts; whereas inhibition of AK017368 had completely opposite effects in vitro. In mice, knockdown of AK017368 promoted muscle hypertrophy in vivo. RNA molecules of AK017368 acted mechanistically as competing endogenous RNAs to target micro‐RNA (miR)‐30c, which was supported by the results of bioinformatics analyses and dual‐luciferase reporter assays. It has been shown that lncRNA AK017368 competes with trinucleotide repeat containing‐6A (Tnrc6a)for miR‐30c. Tnrc6a was previously reported to promote proliferation and inhibit differentiation of myoblast cells, whereas miR‐30c targets the 3'‐UTR of Tnrc6a mRNA to weaken its function. Taken together, lncRNA AK017368 promotes proliferation and inhibits differentiation of myoblast cells by attenuating function of miR‐30c.—Liang, T., Zhou, B., Shi, L., Wang, H., Chu, Q., Xu, F., Li, Y., Chen, R., Shen, C., Schinckel, A. P. lncRNA AK017368 promotes proliferation and suppresses differentiation of myoblasts in skeletal muscle devel‐opment by attenuating the function of miR‐30c. FASEB J. 32,377‐389 (2018). www.fasebj.org
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
While muscle regeneration has been extensively studied in animal and cell culture models, in vivo myogenesis in adult human skeletal muscle has not been investigated in detail.
Using forced ...lengthening contractions induced by electrical stimulation, we induced myofibre injury in young healthy males. Muscle biopsies were collected from the injured leg 7 and 30 days after muscle injury and from the uninjured leg as a control. Immuno-stained single muscle fibres and muscle cross sections were studied by wide-field and confocal microscopy. Samples were also studied at the ultra-structural level by electron microscopy.
Microscopy of single muscle fibres in 3 dimensions revealed a repeating pattern of necrotic and regenerating zones along the length of the same myofibre, characterised by extensive macrophage infiltration alongside differentiating myogenic progenitor cells and myotubes: the hallmarks of myogenesis. The myofibre basement membrane was preserved during these processes and interestingly was seen at a later stage as a second basement membrane surrounding the regenerating fibres.
This is the first work to document in vivo myogenesis in humans in detail and highlights the importance of the basement membrane in the process of regeneration. In addition, it provides insight into parallels between the regeneration of adult skeletal muscle in mouse and man, confirming that this model may be a useful tool in investigating myofibre and matrix formation, as well as specific cell types, during regeneration from the perspective of human muscle.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Formations of myofibers, osteoclasts, syncytiotrophoblasts, and fertilized zygotes share a common step, cell–cell fusion. Recent years have brought about considerable progress in identifying some of ...the proteins involved in these and other cell-fusion processes. However, even for the best-characterized cell fusions, we still do not know the mechanisms that regulate the timing of cell-fusion events. Are they fully controlled by the expression of fusogenic proteins or do they also depend on some triggering signal that activates these proteins? The latter scenario would be analogous to the mechanisms that control the timing of exocytosis initiated by Ca2+ influx and virus-cell fusion initiated by low pH- or receptor interaction. Diverse cell fusions are accompanied by the nonapoptotic exposure of phosphatidylserine at the surface of fusing cells. Here we review data on the dependence of membrane remodeling in cell fusion on phosphatidylserine and phosphatidylserine-recognizing proteins and discuss the hypothesis that cell surface phosphatidylserine serves as a conserved “fuse me” signal regulating the time and place of cell-fusion processes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Regulation of skeletal myogenesis by microRNAs Xu, Meng; Chen, Xiaoling; Chen, Daiwen ...
Journal of cellular physiology,
January 2020, 2020-Jan, 2020-01-00, 20200101, Volume:
235, Issue:
1
Journal Article
Peer reviewed
Skeletal muscle development is a highly organized process controlled by evolutionarily conserved networks of transcription factors, transferrable signaling molecules, and noncoding RNAs that ...coordinate the expression of large numbers of genes. MicroRNAs (miRNAs) have emerged as prominent players of multiple biological processes by silence of specific mRNAs or by suppression of protein translation. It has become to be clear cumulatively that miRNAs control of expression of gene targets are particularly important during skeletal myogenesis. Signaling pathways, especially IGF/AKT/mTOR pathway and TGF‐β signaling, have also determined to act as critical regulators in the regulation of myogenic program. In the last decades, growing evidence has seen a rapid expansion of our knowledge of miRNA‐mediated control of expression of target genes and signaling pathways, in which miRNAs coordinately regulate myogenic process through their targets or through signaling pathways. Here, we summarize the current findings of miRNAs and signaling pathways in the regulation of skeletal myogenesis, focusing on miRNAs’ target genes and IGF/AKT/mTOR pathway and TGF‐β signaling.
(1) We summarize the current findings of microRNAs (miRNAs) and signaling pathways in the regulation of skeletal myogenesis. (2) miRNAs control IGF/AKT/mTOR pathway in skeletal myogenesis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Recent studies indicate important roles for long noncoding RNAs (lncRNAs) as essential regulators of myogenesis and adult skeletal muscle regeneration. However, the specific roles of lncRNAs in ...myogenic differentiation of adult skeletal muscle stem cells and myogenesis are still largely unknown. Here we identify a lncRNA that is specifically enriched in skeletal muscle (myogenesis-associated lncRNA, in short, lnc-mg). In mice, conditional knockout of lnc-mg in skeletal muscle results in muscle atrophy and the loss of muscular endurance during exercise. Alternatively, skeletal muscle-specific overexpression of lnc-mg promotes muscle hypertrophy. In vitro analysis of primary skeletal muscle cells shows that lnc-mg increases gradually during myogenic differentiation and its overexpression improves cell differentiation. Mechanistically, lnc-mg promotes myogenesis, by functioning as a competing endogenous RNA (ceRNA) for microRNA-125b to control protein abundance of insulin-like growth factor 2. These findings identify lnc-mg as a novel noncoding regulator for muscle cell differentiation and skeletal muscle development.
The study aimed to reveal the multi potentials of placenta choriodecidual membranes-derived-mesenchymal stem/stromal cells (pcMSCs) for decidualization and angio-myogenesis. Our previous studies have ...identified a unique type of MSCs, termed pcMSCs, derived from the maternal part of the choriodecidual membrane of the placenta. Unlike other MSCs, pcMSCs express estrogen receptor (ER) and progesterone receptor (PR), crucial for endometrial functions like decidualization. Thus, we hypothesized that pcMSCs may suitable for angiogenesis in the disease model.
In this study, pcMSCs were isolated from human placenta, which involved separating the choriodecidual membrane, finely chopping it, and subjecting it to a digestion buffer with a combination of enzymes, including protease, collagenase B, and DNase-I. These cells were cultured in a serum-free defined medium supplemented with insulin-transferrin-selenium, epidermal growth factor and cultured onto collagen IV-coated dishes. These pcMSCs could be maintained for approximately 18-20 passages in continuous culture. To induce the in vitro decidualization, hormone (estrogen and progesterone) or chemicals (8-Bromo-cAMP/medroxyprogesterone 17-acetate (MPA)) were used, and the morphology and the expression of decidualization markers were assessed. To prove the potentials for angio-myogenesis, the endothelial tube formation assay and critical limb ischemia (CLI) disease animal model were used.
The results indicated that pcMSCs exhibit significant multipotentials for decidualization in vitro when stimulated by estrogen/progesterone or chemical agents like cAMP/MPA, and secrete prolactin and insulin-like growth factor-binding protein-1, biomarkers of decidualization. Additionally, pcMSCs showed pro-angiogenic and muscle regenerating properties, providing therapeutic effects in a CLI mouse model. Within 2-weeks treatment, blood perfusion in the CLI mouse model improved, while muscle atrophy and fibrosis reversed. Activation of satellite cells for muscle repair and increased expression of proteins in the muscle regeneration pathway were observed in the pcMSCs treatment group. Moreover, muscle contraction force following single twitch stimulation (STS) increased post pcMSCs treatment.
These results highlight the decidualization potential of pcMSCs and therapeutic benefits in promoting angiogenesis and muscle regeneration in CLI animal models, emphasizing the importance of selecting the suitable cells for specific indications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The developmental trajectory of human skeletal myogenesis and the transition between progenitor and stem cell states are unclear. We used single-cell RNA sequencing to profile human skeletal muscle ...tissues from embryonic, fetal, and postnatal stages. In silico, we identified myogenic as well as other cell types and constructed a “roadmap” of human skeletal muscle ontogeny across development. In a similar fashion, we also profiled the heterogeneous cell cultures generated from multiple human pluripotent stem cell (hPSC) myogenic differentiation protocols and mapped hPSC-derived myogenic progenitors to an embryonic-to-fetal transition period. We found differentially enriched biological processes and discovered co-regulated gene networks and transcription factors present at distinct myogenic stages. This work serves as a resource for advancing our knowledge of human myogenesis. It also provides a tool for a better understanding of hPSC-derived myogenic progenitors for translational applications in skeletal muscle-based regenerative medicine.
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•Human atlas of limb skeletal muscle in embryonic, fetal, and adult tissues•Human limb skeletal muscle populations and supportive cells vary across development•PAX7 muscle progenitor and stem cells are not identical across developmental states•hPSC-PAX7 cells align to the embryonic-to-fetal transition in human development
Xi et al. developed a comprehensive view of skeletal muscle and supportive cells across human development. This atlas revealed transcriptional differences among myogenic progenitors and stem cells at distinct developmental stages. This enabled identification of the developmental status of hPSC-derived muscle cells to the embryonic-to-fetal transition period in human development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The development and growth of vertebrate axial muscle have been studied for decades at both the descriptive and molecular level. The zebrafish has provided an attractive model system for ...investigating both muscle patterning and growth due to its simple axial musculature with spatially separated fibre types, which contrasts to complex muscle groups often deployed in amniotes. In recent years, new findings have reshaped previous concepts that define how final teleost muscle form is established and maintained. Here, we summarise recent findings in zebrafish embryonic myogenesis with a focus on fibre type specification, followed by an examination of the molecular mechanisms that control muscle growth with emphasis on the role of the dermomyotome-like external cell layer. We also consider these data sets in a comparative context to gain insight into the evolution of axial myogenic patterning systems within the vertebrate lineage.
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