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International Journal of Molecular... Nov 2023Fibroblast growth factor 21 (FGF21) plays a vital role in normal eukaryotic organism development and homeostatic metabolism under the influence of internal and external... (Review)
Review
Fibroblast growth factor 21 (FGF21) plays a vital role in normal eukaryotic organism development and homeostatic metabolism under the influence of internal and external factors such as endogenous hormone changes and exogenous stimuli. Over the last few decades, comprehensive studies have revealed the key role of FGF21 in regulating many fundamental metabolic pathways, including the muscle stress response, insulin signaling transmission, and muscle development. By coordinating these metabolic pathways, FGF21 is thought to contribute to acclimating to a stressful environment and the subsequent recovery of cell and tissue homeostasis. With the emphasis on FGF21, we extensively reviewed the research findings on the production and regulation of FGF21 and its role in muscle metabolism. We also emphasize how the FGF21 metabolic networks mediate mitochondrial dysfunction, glycogen consumption, and myogenic development and investigate prospective directions for the functional exploitation of FGF21 and its downstream effectors, such as the mammalian target of rapamycin (mTOR).
Topics: Prospective Studies; Fibroblast Growth Factors; Signal Transduction; Muscles
PubMed: 38069273
DOI: 10.3390/ijms242316951 -
Cell Proliferation Feb 2024Alternative splicing (AS) disruption has been linked to disorders of muscle development, as well as muscular atrophy. However, the precise changes in AS patterns that...
Alternative splicing (AS) disruption has been linked to disorders of muscle development, as well as muscular atrophy. However, the precise changes in AS patterns that occur during myogenesis are not well understood. Here, we employed isoform long-reads RNA-seq (Iso-seq) and single-cell RNA-seq (scRNA-seq) to investigate the AS landscape during myogenesis. Our Iso-seq data identified 61,146 full-length isoforms representing 11,682 expressed genes, of which over 52% were novel. We identified 38,022 AS events, with most of these events altering coding sequences and exhibiting stage-specific splicing patterns. We identified AS dynamics in different types of muscle cells through scRNA-seq analysis, revealing genes essential for the contractile muscle system and cytoskeleton that undergo differential splicing across cell types. Gene-splicing analysis demonstrated that AS acts as a regulator, independent of changes in overall gene expression. Two isoforms of splicing factor TRA2B play distinct roles in myogenic differentiation by triggering AS of TGFBR2 to regulate canonical TGF-β signalling cascades differently. Our study provides a valuable transcriptome resource for myogenesis and reveals the complexity of AS and its regulation during myogenesis.
Topics: Alternative Splicing; Protein Isoforms; RNA Splicing; Transcriptome; Muscle Development; Gene Expression Profiling
PubMed: 37705195
DOI: 10.1111/cpr.13545 -
Biological Reviews of the Cambridge... Mar 2024Myofibres serve as the functional unit for locomotion, with the sarcomere as fundamental subunit. Running the entire length of this structure are hundreds of myonuclei,...
Myofibres serve as the functional unit for locomotion, with the sarcomere as fundamental subunit. Running the entire length of this structure are hundreds of myonuclei, located at the periphery of the myofibre, juxtaposed to the plasma membrane. Myonuclear specialisation and clustering at the centre and ends of the fibre are known to be essential for muscle contraction, yet the molecular basis of this regionalisation has remained unclear. While the 'myonuclear domain hypothesis' helped explain how myonuclei can independently govern large cytoplasmic territories, novel technologies have provided granularity on the diverse transcriptional programs running simultaneously within the syncytia and added a new perspective on how myonuclei communicate. Building upon this, we explore the critical cellular and molecular sources of transcriptional and functional heterogeneity within myofibres, discussing the impact of intrinsic and extrinsic factors on myonuclear programs. This knowledge provides new insights for understanding muscle development, repair, and disease, but also opens avenues for the development of novel and precise therapeutic approaches.
PubMed: 38477382
DOI: 10.1111/brv.13063 -
Cell Metabolism Jun 2024Diabetes represents a major public health concern with a considerable impact on human life and healthcare expenditures. It is now well established that diabetes is... (Review)
Review
Diabetes represents a major public health concern with a considerable impact on human life and healthcare expenditures. It is now well established that diabetes is characterized by a severe skeletal muscle pathology that limits functional capacity and quality of life. Increasing evidence indicates that diabetes is also one of the most prevalent disorders characterized by impaired skeletal muscle regeneration, yet underlying mechanisms and therapeutic treatments remain poorly established. In this review, we describe the cellular and molecular alterations currently known to occur during skeletal muscle regeneration in people with diabetes and animal models of diabetes, including its associated comorbidities, e.g., obesity, hyperinsulinemia, and insulin resistance. We describe the role of myogenic and non-myogenic cell types on muscle regeneration in conditions with or without diabetes. Therapies for skeletal muscle regeneration and gaps in our knowledge are also discussed, while proposing future directions for the field.
Topics: Humans; Muscle, Skeletal; Regeneration; Animals; Diabetes Mellitus; Muscle Development; Insulin Resistance
PubMed: 38490209
DOI: 10.1016/j.cmet.2024.02.014 -
Scientific Reports Dec 2023Obesity has been increasing in many regions of the world, including Europe, USA, and Korea. To manage obesity, we should consider it as a disease and apply therapeutic...
Obesity has been increasing in many regions of the world, including Europe, USA, and Korea. To manage obesity, we should consider it as a disease and apply therapeutic methods for its treatment. Molecular and therapeutic approaches for obesity management involve regulating biomolecules such as DNA, RNA, and protein in adipose-derived stem cells to prevent to be fat cells. Multiple factors are believed to play a role in fat differentiation, with one of the most effective factor is Ca. We recently reported that the electromagnetic perceptive gene (EPG) regulated intracellular Ca levels under various electromagnetic fields. This study aimed to investigate whether EPG could serve as a therapeutic method against obesity. We confirmed that EPG serves as a modulator of Ca levels in primary adipose cells, thereby regulating several genes such as CasR, PPARγ, GLU4, GAPDH during the adipogenesis. In addition, this study also identified EPG-mediated regulation of myogenesis that myocyte transcription factors (CasR, MyoG, MyoD, Myomaker) were changed in C2C12 cells and satellite cells. In vivo experiments carried out in this study confirmed that total weight/ fat/fat accumulation were decreased and lean mass was increased by EPG with magnetic field depending on age of mice. The EPG could serve as a potent therapeutic agent against obesity.
Topics: Animals; Mice; 3T3-L1 Cells; Adipogenesis; Cell Differentiation; Electromagnetic Phenomena; Muscle Development; Obesity; PPAR gamma; Fish Proteins
PubMed: 38036595
DOI: 10.1038/s41598-023-48360-6 -
Animal Biotechnology Dec 2023CircRNAs are a novel type of closed circular molecules formed through a covalent bond lacking a 5'cap and 3' end tail, which mainly arise from mRNA precursor. They are... (Review)
Review
CircRNAs are a novel type of closed circular molecules formed through a covalent bond lacking a 5'cap and 3' end tail, which mainly arise from mRNA precursor. They are widely distributed in plants and animals and are characterized by stable structure, high conservativeness in cells or tissues, and showed the expression specificity at different stages of development in different tissues. CircRNAs have been gradually attracted wide attention with the development of RNA sequencing, which become a new research hotspot in the field of RNA. CircRNAs play an important role in gene expression regulation. Presently, the related circRNAs research in the regulation of animal muscle development is still at the initial stage. In this review, the formation, properties, biological functions of circRNAs were summarized. The recent research progresses of circRNAs in skeletal muscle growth and development from economic animals including livestock, poultry and fishes were introduced. Finally, we proposed a prospective for further studies of circRNAs in muscle development, and we hope our research could provide new ideas, some theoretical supports and helps for new molecular genetic markers exploitation and animal genetic breeding in future.
Topics: Animals; RNA, Circular; Prospective Studies; RNA; Genetic Markers; Muscle Development
PubMed: 36052979
DOI: 10.1080/10495398.2022.2118130 -
Trends in Molecular Medicine Mar 2024Earlier evidence that targeting the balance between histone acetyltransferases (HATs) and deacetylases (HDACs), through exposure to HDAC inhibitors (HDACis), could... (Review)
Review
Earlier evidence that targeting the balance between histone acetyltransferases (HATs) and deacetylases (HDACs), through exposure to HDAC inhibitors (HDACis), could enhance skeletal myogenesis, prompted interest in using HDACis to promote muscle regeneration. Further identification of constitutive HDAC activation in dystrophin-deficient muscles, caused by dysregulated nitric oxide (NO) signaling, provided the rationale for HDACi-based therapeutic interventions for Duchenne muscular dystrophy (DMD). In this review, we describe the molecular, preclinical, and clinical evidence supporting the efficacy of HDACis in countering disease progression by targeting pathogenic networks of gene expression in multiple muscle-resident cell types of patients with DMD. Given that givinostat is paving the way for HDACi-based interventions in DMD, next-generation HDACis with optimized therapeutic profiles and efficacy could be also explored for synergistic combinations with other therapeutic strategies.
Topics: Mice; Animals; Humans; Muscular Dystrophy, Duchenne; Histone Deacetylase Inhibitors; Muscle, Skeletal; Mice, Inbred mdx; Dystrophin; Signal Transduction
PubMed: 38408879
DOI: 10.1016/j.molmed.2024.01.007 -
JSES Reviews, Reports, and Techniques Aug 2023Traumatic or degenerative rotator cuff (RC) tendon injuries are a leading cause of persistent shoulder pain and reduction of mobility with associated disability and... (Review)
Review
Traumatic or degenerative rotator cuff (RC) tendon injuries are a leading cause of persistent shoulder pain and reduction of mobility with associated disability and dysfunction, which require each year more than 250,000 surgical repairs in the United States. MicroRNAs (miRNAs) are small noncoding RNAs, that in the posttranscriptional phase lead to the development and function of tissues. The aim of this review was to identify miRNA expression changes in patients with RC pathologies and to determine their relevance as a potential novel diagnostic and potentially therapeutic tool for RC disorders. Various miRNAs seemed to be key regulators in the muscle architecture, determining several modifications in muscle atrophy, skeletal muscle mechanical adaptation, lipid accumulation, and fibrosis in the presence of RC tears. The search was executed using PubMed, Medline, Scopus, and Cochrane Central. We included studies written in English that evaluated the role of miRNA in diagnosis, physiopathology, and potential therapeutic application of RC tendon injuries. We included 11 studies in this review. Many miRNAs emerged as key regulators in the pathogenesis of RC tears, inflammation, and muscle fatty degeneration. In fact, they are involved in the regulation of myogenesis, inflammatory cytokines, metalloproteases expression, muscle adaptation, adipogenesis, fibrogenic factors, and extracellular matrix synthesis. The gene expression may be altered in the pathological processes of tendon lesions. Therefore, the knowledge of all the gene mechanisms underlying RC tendinopathy should be achieved with future diagnostic and clinical studies.
PubMed: 37588508
DOI: 10.1016/j.xrrt.2023.03.006 -
Nature Communications Dec 2023The cellular prion protein (PrP) is required for skeletal muscle function. Here, we report that a higher level of PrP accumulates in the cytoplasm of the skeletal muscle...
The cellular prion protein (PrP) is required for skeletal muscle function. Here, we report that a higher level of PrP accumulates in the cytoplasm of the skeletal muscle of six myopathy patients compared to controls. PrP inhibits skeletal muscle cell autophagy, and blocks myoblast differentiation. PrP selectively binds to a subset of miRNAs during myoblast differentiation, and the colocalization of PrP and miR-214-3p was observed in the skeletal muscle of six myopathy patients with excessive PrP. We demonstrate that PrP is overexpressed in skeletal muscle cells under pathological conditions, inhibits muscle cell differentiation by physically interacting with a subset of miRNAs, and selectively recruits these miRNAs into its phase-separated condensate in living myoblasts, which in turn enhances liquid-liquid phase separation of PrP, promotes pathological aggregation of PrP, and results in the inhibition of autophagy-related protein 5-dependent autophagy and muscle bundle formation in myopathy patients characterized by incomplete muscle regeneration.
Topics: Humans; Cell Differentiation; Cell Proliferation; MicroRNAs; Muscle Development; Muscle, Skeletal; Muscular Diseases; PrPC Proteins
PubMed: 38065962
DOI: 10.1038/s41467-023-43826-7 -
BMC Musculoskeletal Disorders Jul 2023Osteoporosis is a worldwide health issue. Loss of bone mass is a potential risk factor for fragility fractures, and osteoporotic fractures place a considerable burden on...
BACKGROUND
Osteoporosis is a worldwide health issue. Loss of bone mass is a potential risk factor for fragility fractures, and osteoporotic fractures place a considerable burden on society. Bone and muscle represent a functional unit in which the two tissues are intimately interconnected. Ropivacaine is a potent local anesthetic used in clinical practice for intraoperative anesthesia and postoperative pain management, in particular for hip surgery. When injected, Ropivacaine can diffuse locally through, in particular in surrounding skeletal muscle tissue, causing dose-dependent cytotoxicity, oxidative stress and myogenesis impairment. Based on those evidences, we focused our attention on Ropivacaine-induced cytotoxicity on cultured human myoblasts.
METHODS
Primary human myoblasts and myotubes from healthy subjects, osteoarthritic and osteoporotic patients (OP) were cultured in the presence of Ropivacaine. In some experiments, ascorbic acid (AsA) was added as a potent antioxidant agent. Cell viability and ROS levels were evaluated to investigate the myotoxic activity and Real-Time PCR and Western blot analysis carried out to investigate the expression of proliferation and myogenic markers.
RESULTS
A dose-dependent decrease of cell viability was observed after Ropivacaine exposure in both OP myoblasts and myotubes cultures, whereas those effects were not observed in the presence of Propofol, a general anesthetic. The adding of AsA reduced Ropivacaine negative effects in OP myoblast cultures. In addition, Ropivacaine exposure also increased ROS levels and upregulated Nox4 expression, an enzyme primarily implicated in skeletal muscle ROS generation. AsA treatment counteracted the oxidant activity of Ropivacaine and partially restored the basal condition in cultures. Positive myogenic markers, such as MyoD and Myf5, were downregulated by Ropivacaine exposure, whereas myostatin, a negative regulator of muscle growth and differentiation, was upregulated. The phenotypic deregulation of myogenic controllers in the presence of Ropivacaine was counteracted by AsA treatment.
CONCLUSIONS
Our findings highlight the oxidative stress-mediated myotoxic effect of Ropivacaine on human skeletal muscle tissue cell cultures, and suggest treatment with AsA as valid strategy to mitigate its negative effects and allowing an ameliorated functional skeletal muscle recovery in patients undergoing hip replacement surgery for osteoporotic bone fracture.
Topics: Humans; Ropivacaine; Myotoxicity; Ascorbic Acid; Reactive Oxygen Species; Cells, Cultured; Muscle Fibers, Skeletal; Muscle, Skeletal; Cell Differentiation; Muscle Development
PubMed: 37454045
DOI: 10.1186/s12891-023-06702-5