Regulation Of Myogenesis Research Articles

Biological sex divergence in transcriptomic profiles during the onset of hindlimb unloading-induced atrophy.

Disuse-induced muscle atrophy is a common clinical problem observed mainly in older adults, intensive care units patients, or astronauts. Previous studies presented biological sex divergence in progression of disuse-induced atrophy along with differential changes in molecular mechanisms possibly underlying muscle atrophy. The aim of this study was to perform transcriptomic profiling of male and female mice during the onset and progression of unloading disuse-induced atrophy. Male and female mice underwent hindlimb unloading (HU) for 24, 48, 72, and 168 h (n = 8/group). Muscles were weighed for each cohort and gastrocnemius was used for RNA-sequencing analysis. Females exhibited muscle loss as early as 24 h of HU, whereas males after 168 h of HU. In males, pathways related to proteasome degradation were upregulated throughout 168 h of HU, whereas in females these pathways were upregulated up to 72 h of HU. Lcn2, a gene contributing to regulation of myogenesis, was upregulated by 6.46- to 19.86-fold across all time points in females only. A reverse expression of Fosb, a gene related to muscle degeneration, was observed between males (4.27-fold up) and females (4.57-fold down) at 24-h HU. Mitochondrial pathways related to tricarboxylic acid (TCA) cycle were highly downregulated at 168 h of HU in males, whereas in females this downregulation was less pronounced. Collagen-related pathways were consistently downregulated throughout 168 h of HU only in females, suggesting a potential biological sex-specific protective mechanism against disuse-induced fibrosis. In conclusion, females may have protection against HU-induced skeletal muscle mitochondrial degeneration and fibrosis through transcriptional mechanisms, although they may be more vulnerable to HU-induced muscle wasting compared with males.NEW & NOTEWORTHY Herein, we have assessed the transcriptomic response across biological sexes during the onset and progression of unloading disuse-induced atrophy in mice. We have demonstrated an inverse expression of Fosb between males and females, as well as differentially timed patterns of expressing atrophy-related pathways between sexes that are concomitant to the accelerated atrophy in females. We also identified in females signs of mechanisms to combat disuse-induced mitochondrial degeneration and fibrosis.

Ythdf2-mediated STK11 mRNA decay supports myogenesis by inhibiting the AMPK/mTOR pathway

An emerging research focus is the role of m6A modifications in mediating the post-transcriptional regulation of mRNA during mammalian development. Recent evidence suggests that m6A methyltransferases and demethylases play critical roles in skeletal muscle development. Ythdf2 is a m6A “reader” protein that mediates mRNA degradation in an m6A-dependent manner. However, the specific function of Ythdf2 in skeletal muscle development and the underlying mechanisms remain unclear. Here, we observed that Ythdf2 expression was significantly upregulated during myogenic differentiation, whereas Ythdf2 knockdown markedly inhibited myoblast proliferation and differentiation. Combined analysis of high-throughput sequencing, Co-IP, and RIP assay revealed that Ythdf2 could bind to m6A sites in STK11 mRNA and form an Ago2 silencing complex to promote its degradation, thereby regulating its expression and consequently, the AMPK/mTOR pathway. Furthermore, STK11 downregulation partially rescued Ythdf2 knockdown-induced impairment of proliferation and myogenic differentiation by inhibiting the AMPK/mTOR pathway. Collectively, our results indicate that Ythdf2 mediates the decay of STK11 mRNA, an AMPK activator, in an Ago2 system-dependent manner, thereby driving skeletal myogenesis by suppressing the AMPK/mTOR pathway. These findings further enhance our understanding of the molecular mechanisms underlying RNA methylation in the regulation of myogenesis and provide valuable insights for conducting in-depth studies on myogenesis.

Expression profile and bioinformatics analysis of circRNA and its associated ceRNA networks in longissimus dorsi from Lufeng cattle and Leiqiong cattle

This paper aims to explore the role of circRNA expression profiles and circRNA-associated ceRNA networks in the regulation of myogenesis in the longissimus dorsi of cattle breeds surviving under subtropical conditions in southern China by RNA sequencing and bioinformatics analysis. It also aims to provide comprehensive understanding of the differences in muscle fibers in subtropical cattle breeds and to expand the knowledge of the molecular networks that regulate myogenesis. With regard to meat quality indicators, results showed that the longissimus dorsi of LQC had lower pH (P < 0.0001), lower redness (P < 0.01), lower shear force (P < 0.05), and higher brightness (P < 0.05) than the longissimus dorsi of LFC. With regard to muscle fiber characteristics, the longissimus dorsi of LQC had a smaller diameter (P < 0.0001) and higher density of muscle fibers (P < 0.05). The analysis results show that the function of many circRNA-targeted mRNAs was related to myogenesis and metabolic regulation. Furthermore, in the analysis of the function of circRNA source genes, we hypothesized that btacirc_00497 and btacirc_034497 may regulate the function and type of myofibrils by affecting the expression of MYH6, MYH7, and NEB through competitive linear splicing.

Diagnosis and treatment of rhabdomyosarcomas

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma. The primary tumor is most commonly localized in the head and neck, the urogenital system, or the limbs. Classification by the World Health Organization has distinguished four histopathological RMS subtypes: embryonal, alveolar, pleomorphic, and spindle cell/sclerosing. Differential diagnosis of RMS includes melanoma, malignant neoplasm of peripheral nerve sheaths, liposarcoma, and PEComa. Among typical cytogenetic changes in RMS are chromosomal translocations t(2;13)(q35;q14) and t(1;13) (p36;q14). They lead to the formation of fusion genes that have a prognostic value. In the course of RMS, changes may also be present in signaling pathways, including RAS-PI3K, Wnt/b-catenin, receptor tyrosine kinase pathways, and myogenesis regulation. In 30% of patients at the time of diagnosis of RMS, distant metastases are present, most commonly to lungs, lymph nodes, bones, and bone marrow. Treatment of patients with RMS requires a multidisciplinary approach, and steadily perfected diagnostic techniques contribute to the individualization of therapeutic strategies. Optimal treatment of localized RMS is based on surgery combined with radiotherapy and chemotherapy. If distant metastases are present, the basic therapeutic method is multidrug chemotherapy, most frequently based on vincristine, dactinomycin, ifosfamide/cyclophosphamide, and etoposide. Despite intensive treatment, the 5-year survival index for RMS is not greater than 50%. There are still no unequivocal guidelines concerning the treatment in patients with local or distant recurrences.

Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD

Lack of dystrophin expression is the underlying genetic basis for Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2-mdx muscles is associated with an enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports the excessive accumulation of fibroadipogenic progenitors (FAPs), leading to increased fibrosis. Unexpectedly, the extent of damage and degeneration in juvenile D2-mdx muscle is significantly reduced in adults, and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance regenerative myogenesis in the adult D2-mdx muscle, reaching levels comparable to the milder B10-mdx model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with juvenile D2-mdx FAPs reduces their fusion efficacy. Wild-type juvenile D2 mice also manifest regenerative myogenic deficit and glucocorticoid treatment improves their muscle regeneration. Our findings indicate that aberrant stromal cell responses contribute to poor regenerative myogenesis and greater muscle degeneration in juvenile D2-mdx muscles and reversal of this reduces pathology in adult D2-mdx muscle, identifying these responses as a potential therapeutic target for the treatment of DMD.

PARP1 mediated PARylation contributes to myogenic progression and glucocorticoid transcriptional response

The ADP-ribosyltransferase, PARP1 enzymatically generates and applies the post-translational modification, ADP-Ribose (ADPR). PARP1 roles in genome maintenance are well described, but recent work highlights roles in many fundamental processes including cellular identity and energy homeostasis. Herein, we show in both mouse and human skeletal muscle cells that PARP1-mediated PARylation is a regulator of the myogenic program and the muscle transcriptional response to steroid hormones. Chemical PARP1 modulation impacts the expression of major myocellular proteins, including troponins, key in dictating muscle contractile force. Whilst PARP1 in absence of DNA damage is often assumed to be basally inactive, we show PARylation to be acutely sensitive to extracellular glucose concentrations and the steroid hormone class, glucocorticoids which exert considerable authority over muscle tissue mass. Specifically, we find during myogenesis, a transient and significant rise in PAR. This early-stage differentiation event, if blocked with PARP1 inhibition, reduced the abundance of important muscle proteins in the fully differentiated myotubes. This suggests that PAR targets during early-stage differentiation are central to the proper development of the muscle contractile unit. We also show that reduced PARP1 in myoblasts impacts a variety of metabolic pathways in line with the recorded actions of glucocorticoids. Currently, as both regulators of myogenesis and muscle mass loss, glucocorticoids represent a clinical conundrum. Our work goes on to identify that PARP1 influences transcriptional activation by glucocorticoids of a subset of genes critical to human skeletal muscle pathology. These genes may therefore signify a regulatory battery of targets through which selective glucocorticoid modulation could be achieved. Collectively, our data provide clear links between PARP1-mediated PARylation and skeletal muscle homeostatic mechanisms crucial to tissue mass maintenance and endocrine response.

CircRRAS2 promotes myogenic differentiation of bovine MuSCs and is a novel regulatory molecule of muscle development

The proliferation and myogenic differentiation of muscle stem cells (MuSCs) are important factors affecting muscle development and beef quality. There is increasing evidence that circRNAs can regulate myogenesis. We found a novel circRNA, named circRRAS2 that is significantly upregulated in the differentiation phase of bovine MuSCs. Here, we aimed to determine its roles in the proliferation and myogenic differentiation of these cells. The results showed that circRRAS2 was expressed in several bovine tissues. CircRRAS2 inhibited MuSCs proliferation and promoted myoblast differentiation. In addition, chromatin isolation by using RNA purification and mass spectrometry in differentiated muscle cells identified 52 RNA-binding proteins that could potentially bind to circRRAS2, in order to regulate their differentiation. The results suggest that circRRAS2 could be a specific regulator of myogenesis in bovine muscle. Highlights CircRRAS2 expression is higher in DM cells than in GM cells. CircRRAS2 could significantly inhibit the proliferation and apoptosis of bovine MuSCs. CircRRAS2 promotes the differentiation of bovine MuSCs into myotubes. CircRRAS2 may exert regulatory effects through multiple RNA binding proteins.

Odd skipped-related 1 controls the pro-regenerative response of fibro-adipogenic progenitors

Skeletal muscle regeneration requires the coordinated interplay of diverse tissue-resident- and infiltrating cells. Fibro-adipogenic progenitors (FAPs) are an interstitial cell population that provides a beneficial microenvironment for muscle stem cells (MuSCs) during muscle regeneration. Here we show that the transcription factor Osr1 is essential for FAPs to communicate with MuSCs and infiltrating macrophages, thus coordinating muscle regeneration. Conditional inactivation of Osr1 impaired muscle regeneration with reduced myofiber growth and formation of excessive fibrotic tissue with reduced stiffness. Osr1-deficient FAPs acquired a fibrogenic identity with altered matrix secretion and cytokine expression resulting in impaired MuSC viability, expansion and differentiation. Immune cell profiling suggested a novel role for Osr1-FAPs in macrophage polarization. In vitro analysis suggested that increased TGFβ signaling and altered matrix deposition by Osr1-deficient FAPs actively suppressed regenerative myogenesis. In conclusion, we show that Osr1 is central to FAP function orchestrating key regenerative events such as inflammation, matrix secretion and myogenesis.

Міокіни – один із ключових елементів взаємодії між скелетними м'язами та іншими системами організму людини, необхідних для адаптації до фізичних навантажень

Muscle tissue makes up a significant percentage of body weight, and its metabolism affects almost all body systems. Despite a sufficiently large number of physiological observations that confirmed the need for regular physical activity to maintain health, the molecular mechanisms of such an effect remained unestablished for a long time. Results of recent research confirmed that skeletal muscles are an endocrine organ that produces a wide range of bioregulators, which synthesis and excretion are stimulated during exercise. At present, many of these factors that mediate metabolic and physiological responses in muscles and other organs have been identified and named myokines. To date the most studied myokines are: interleukins (IL-6, LIF, IL-4, IL-7, IL-8, and IL-15), myostatin, myonectin (CTRP15), irisin, fibroblast growth factor 21 (FGF21), brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), follistatin-like protein-1 (FSTL-1), decorin and SPARC (osteonectin). Most of the myokines exert their effects through paracrine and/or autocrine pathways within muscles, and many of them also act as endocrine agents – via lymph and blood. The biological activity of myokines is realized via modulation of the activity of general global regulatory mechanisms, such as the SMAD signaling cascade, p38/MAPK, Erk1/2 MAPK, PI3K/Akt/GSK-3β, cAMP/Akt, AMPK-dependent regulation, and JNK signaling pathway. At the same time, myokines are involved in the regulation of the activity of the myogenic transcription factors MyoD, myf5, myogenin and a number of proteins involved in the sensing and transport of glucose and fatty acids. Myokines play one of the main roles in the interaction between skeletal muscles, liver, bone and adipose tissues. They increase tissues sensitivity to insulin and are involved in the regulation of important metabolic processes such as carbohydrate, protein and lipid metabolism. Myokines play a significant role in the regulation of myogenesis, osteogenesis, thermogenesis, lipolysis, growth and division of muscle and nerve tissue cells, vascularization, etc. Given the fact that the expression of myokines is induced by muscle contraction, their study allows us to reveal the molecular mechanisms realizing the positive effects of physical exertion. Further studies of myokines and their mechanisms of action are necessary for the development of personalized recommendations for the physical activity of people with metabolic diseases in rehabilitation, physical therapy, medical supervision of physical education and sports.

Transcriptome RNA Sequencing Reveals That Circular RNAs Are Abundantly Expressed in Embryonic Breast Muscle of Duck.

Circular RNAs are widespread in various species and have important roles in myogenesis. However, the circular RNAs involved in breast muscle development in ducks have not yet been studied. Here, to identify circular RNAs during duck skeletal muscle development, three pectorales from Shan Ma ducks at E13 and E19, which represent undifferentiated and differentiated myoblasts, respectively, were collected and subjected to RNA sequencing. A total of 16,622 circular RNAs were identified, of which approximately 80% were exonic circular RNAs and 260 were markedly differentially expressed between E19 and E13. The parental genes of the differentially expressed circular RNAs were significantly enriched in muscle-related biological processes. Moreover, we found that the overexpression of circGAS2-2 promoted cell cycle progression and increased the proliferation viability of duck primary myoblasts; conversely, knockdown of circGAS2-2 retarded the cell cycle and reduced the proliferation viability of myoblasts. Taken together, our results demonstrate that circular RNAs are widespread and variously expressed during the development of duck skeletal muscle and that circGAS2-2 is involved in the regulation of myogenesis.

Nuclear factor 1 X-type-associated regulation of myogenesis in developing mouse tongue

ObjectivesThe tongue contains skeletal myofibers that differ from those in the trunk, limbs, and other orofacial muscles. However, the molecular basis of myogenic differentiation in the tongue muscles remains unclear. In this study, we conducted comprehensive gene expression profiling of the developing murine tongue. MethodsTongue primordia were dissected from mouse embryos at embryonic day (E)10.5–E18.5, while myogenic markers were detected via microarray analysis and quantitative polymerase chain reaction (PCR). In addition to common myogenic regulatory factors such as Myf5, MyoD, myogenin, and Mrf4, we focused on Nfix, which acts as a unique molecular switch triggering the shift from embryonic to fetal myoblast lineage during limb myogenesis. Nfix inhibition was performed using a specific antisense oligonucleotide in the organ culture of tongue primordia. ResultsMicroarray and ingenuity pathway analyses confirmed the significant upregulation of myogenic signaling molecules, including Nfix, associated with the differentiation of myoblasts from myogenic progenitor cells during E10.5–E11.5. Quantitative PCR confirmed that Nfix expression started at E10.5 and peaked at E14.5. Fetal myoblast-specific genes, such as Mck and Myh8, were upregulated after E14.5, whereas embryonic myoblast-specific genes, such as Myh3 and Myh7, were downregulated. When Nfix was inhibited in the organ culture of tongue primordia, subtle morphological differences were noted in the tongue. Such an observation was only noted in the cultures of E10.5-derived tongue primordia. ConclusionsThese results reveal the contribution of Nfix to tongue myogenesis. Nfix expression during early tongue development may play a vital role in tongue muscle development.

Loss of CRY2 promotes regenerative myogenesis by enhancing PAX7 expression and satellite cell proliferation.

The regenerative capacity of skeletal muscle is dependent on satellite cells. The circadian clock regulates the maintenance and function of satellite cells. Cryptochrome 2 (CRY2) is a critical component of the circadian clock, and its role in skeletal muscle regeneration remains controversial. Using the skeletal muscle lineage and satellite cell-specific CRY2 knockout mice (CRY2scko), we show that the deletion of CRY2 enhances muscle regeneration. Single myofiber analysis revealed that deletion of CRY2 stimulates the proliferation of myoblasts. The differentiation potential of myoblasts was enhanced by the loss of CRY2 evidenced by increased expression of myosin heavy chain (MyHC) and myotube formation in CRY2-/- cells versus CRY2+/+ cells. Immunostaining revealed that the number of mononucleated paired box protein 7 (PAX7+) cells associated with myotubes formed by CRY2-/- cells was increased compared with CRY2+/+ cells, suggesting that more reserve cells were produced in the absence of CRY2. Loss of CRY2 leads to the activation of the ERK1/2 signaling pathway and ETS1, which binds to the promoter of PAX7 to induce its transcription. CRY2 deficient myoblasts survived better in ischemic muscle. Therefore, CRY2 is essential in regulating skeletal muscle repair.

Adiponectin receptors activation performs dual effects on regulating myogenesis and adipogenesis of young and aged muscle satellite cells.

Skeletal muscle mass and function deteriorate with ageing. Adiponectin receptors (APNrs), mainly activated by adiponectin, participate in various physiological activities and have varying signalling pathways at different ages. This study aimed to explore whether discrepant performance exists in APNr activation regulating young and aged muscle satellite cells (MUSCs) and whether age-related muscle dysfunction could be alleviated upon APNr activation. The gastrocnemius muscle phenotype was observed in male mice aged 2 and 18 months. An APNr agonist (AdipoRon) was used in vitro and in vivo to investigate the changes in cell biological behaviours and whether muscle dysfunction could be retarded after APNr activation. Aged mice exhibited decreased muscle mass and increased fat infiltration. APNr activation inhibited C2C12 cells and young MUSCs (YMUSCs) proliferation but showed no obvious effect on aged MUSCs (AMUSCs). Moreover, APNr activation inhibited the migration of both YMUSCs and AMUSCs. Interestingly, APNr activation hampered the myogenic differentiation but advanced the adipogenic differentiation of YMUSCs, yet exact opposite results were presented in AMUSCs. It was demonstrated that Wnt and PI3K signalling pathways may mediate the phenotypic differences. Furthermore, in vivo experiments verified that APNr activation ameliorated age-related muscle atrophy and excessive fat infiltration. APNr activation exerted dual effects on the regulation of myogenesis and adipogenesis of YMUSCs and AMUSCs and rescued age-related skeletal muscle dysfunction.

Myomaker and Myomixer Characterization in Gilthead Sea Bream under Different Myogenesis Conditions

Skeletal muscle is formed by multinucleated myofibers originated by waves of hyperplasia and hypertrophy during myogenesis. Tissue damage triggers a regeneration process including new myogenesis and muscular remodeling. During myogenesis, the fusion of myoblasts is a key step that requires different genes' expression, including the fusogens myomaker and myomixer. The present work aimed to characterize these proteins in gilthead sea bream and their possible role in in vitro myogenesis, at different fish ages and during muscle regeneration after induced tissue injury. Myomaker is a transmembrane protein highly conserved among vertebrates, whereas Myomixer is a micropeptide that is moderately conserved. myomaker expression is restricted to skeletal muscle, while the expression of myomixer is more ubiquitous. In primary myocytes culture, myomaker and myomixer expression peaked at day 6 and day 8, respectively. During regeneration, the expression of both fusogens and all the myogenic regulatory factors showed a peak after 16 days post-injury. Moreover, myomaker and myomixer were present at different ages, but in fingerlings there were significantly higher transcript levels than in juveniles or adult fish. Overall, Myomaker and Myomixer are valuable markers of muscle growth that together with other regulatory molecules can provide a deeper understanding of myogenesis regulation in fish.

O-GlcNAcylation is a gatekeeper of porcine myogenesis.

Although it has long been known that growth media withdrawal is a prerequisite for myoblast differentiation and fusion, the underpinning molecular mechanism remains somewhat elusive. Using isolated porcine muscle satellite cells (SCs) as the model, we show elevated O-GlcNAcylation by O-GlcNAcase (OGA) inhibition impaired SC differentiation (D5 P < 0.0001) but had unnoticeable impacts on SC proliferation. To explore the mechanism of this phenotype, we examined the expression of the transcription factor myogenin, a master switch of myogenesis, and found its expression was downregulated by elevated O-GlcNAcylation. Because insulin/IGF-1/Akt axis is a strong promoter of myoblast fusion, we measured the phosphorylated Akt and found that hyper O-GlcNAcylation inhibited Akt phosphorylation, implying OGA inhibition may also work through interfering with this critical differentiation-promoting pathway. In contrast, inhibition of O-GlcNAc transferase (OGT) by its specific inhibitor had little impact on either myoblast proliferation or differentiation (P > 0.05). To confirm these in vitro findings, we used chemical-induced muscle injury in the pig as a model to study muscle regenerative myogenesis and showed how O-GlcNAcylation functions in this process. We show a significant decrease in muscle fiber cross sectional area (CSA) when OGA is inhibited (P < 0.05), compared to nondamaged muscle, and a significant decrease compared to control and OGT inhibited muscle (P < 0.05), indicating a significant impairment in porcine muscle regeneration in vivo. Together, the in vitro and in vivo data suggest that O-GlcNAcylation may serve as a nutrient sensor during SC differentiation by gauging cellular nutrient availability and translating these signals into cellular responses. Given the importance of nutrition availability in lean muscle growth, our findings may have significant implications on how muscle growth is regulated in agriculturally important animals.

The INSR/AKT/mTOR pathway regulates the pace of myogenesis in a syndecan-3-dependent manner

Muscle stem cells (MuSCs) are indispensable for muscle regeneration. A multitude of extracellular stimuli direct MuSC fate decisions from quiescent progenitors to differentiated myocytes. The activity of these signals is modulated by coreceptors such as syndecan-3 (SDC3). We investigated the global landscape of SDC3-mediated regulation of myogenesis using a phosphoproteomics approach which revealed, with the precision level of individual phosphosites, the large-scale extent of SDC3-mediated regulation of signal transduction in MuSCs. We then focused on INSR/AKT/mTOR as a key pathway regulated by SDC3 during myogenesis and mechanistically dissected SDC3-mediated inhibition of insulin receptor signaling in MuSCs. SDC3 interacts with INSR ultimately limiting signal transduction via AKT/mTOR. Both knockdown of INSR and inhibition of AKT restore Sdc3−/− MuSC differentiation to wild type levels. Since SDC3 is rapidly downregulated at the onset of differentiation, our study suggests that SDC3 acts a timekeeper to restrain proliferating MuSC response and prevent premature differentiation.

Adipose improves muscular atrophy caused by Sirtuin1 deficiency by promoting mitochondria synthesis

Muscular dysplasia is a common muscle disease, but its pathological mechanism is still unclear. Adipose is originally identified as a highly conservative and widely expressed anti-obesity gene, and our previous study has reported that Adipose is also a positive regulator of myogenesis. Considering the vital role of during muscle development, this study was to demonstrate a potential relationship between Sirtuin1 and Adipose and clarified the mechanism by which Adipose regulated muscle development. Our results showed that the muscle fiber cross-sectional area and myosin heavy chain protein level were significantly reduced in Sirtuin1+/- mice. Moreover, the longitudinal section of muscle fibers was obviously irregular. Sirtuin1 knockdown significantly reduced the expression levels of Adipose and its upstream transcriptional regulator Kruppel like factor 15 and notably inhibited the AMP-activated protein kinase α-peroxisome proliferator-activated receptor gamma coactivator 1α signaling pathway in skeletal muscle. However, Adipose over-expression activated this signaling pathway and promoted mitochondrial biosynthesis in C2C12 myoblasts. Adipose over-expression also enhanced glucose absorption of C2C12 cells, suggesting the increased needs for cells for metabolic substrates. In C2C12 cells with hydrogen peroxide treatment, Adipose over-expression repressed hydrogen peroxide-elicited apoptosis and mitochondrial loss, while Sirtuin1-specific inhibitor dramatically weakened these roles of Adipose. Taken together, our findings reveal that Adipose rescues the adverse effects of Sirtuin1 deficiency or hydrogen peroxide on muscle development by activating the AMP-activated protein kinase α- peroxisome proliferator-activated receptor gamma coactivator 1α pathway to promote mitochondria synthesis, which provides theoretical basis for developing new therapeutic targets against some muscle diseases.

Effects of PGC-1α overexpression on the myogenic response during skeletal muscle regeneration

The ability of skeletal muscle to regenerate from injury is crucial for locomotion, metabolic health, and quality of life. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1A) is a transcriptional coactivator required for mitochondrial biogenesis. Increased mitochondrial biogenesis is associated with improved muscle cell differentiation, however PGC1A's role in skeletal muscle regeneration following damage requires further investigation. The purpose of this study was to investigate the role of skeletal muscle-specific PGC1A overexpression during regeneration following damage. 22 C57BL/6J (WT) and 26 PGC1A muscle transgenic (A1) mice were injected with either phosphate-buffered saline (PBS, uninjured control) or Bupivacaine (MAR, injured) into their tibialis anterior (TA) muscle to induce skeletal muscle damage. TA muscles were extracted 3- or 28-days post-injury and analyzed for markers of regenerative myogenesis and protein turnover. Pgc1a mRNA was ∼10–20 fold greater in A1 mice. Markers of protein synthesis, AKT and 4EBP1, displayed decreases in A1 mice compared to WT at both timepoints indicating a decreased protein synthetic response. Myod mRNA was ∼75% lower compared to WT 3 days post-injection. WT mice exhibited decreased cross-sectional area of the TA muscle at 28 days post-injection with bupivacaine compared to all other groups. PGC1A overexpression modifies the myogenic response during regeneration.

HDAC11 Regulates the Proliferation of Bovine Muscle Stem Cells through the Notch Signaling Pathway and Inhibits Muscle Regeneration.

Myogenesis is an essential process that can affect the yield and quality of beef. Transcriptional studies have shown that histone deacetylase 11 (HDAC11) was differentially expressed in muscle tissues of 6 and 18 month old Longlin cattle, but its role in the regulation of myogenesis remains unclear. This study aimed to determine the role of HDAC11 in the proliferation and differentiation of bovine muscle stem cells (MuSCs). HDAC11 promoted MuSC proliferation by activating Notch signaling and inhibited myoblast differentiation by reducing MyoD1 transcription. In addition, overexpression of HDAC11 inhibited the repair regeneration process of muscle in mice. HDAC11 was found to be a novel key target for the control of myogenesis, and this is a theoretical basis for the development of HDAC11-specific modulators as a new strategy to regulate myogenesis.

CircMEF2D Negatively Regulated by HNRNPA1 Inhibits Proliferation and Differentiation of Myoblasts via miR-486-PI3K/AKT Axis.

Circular RNA (circRNA) is a form of endogenous RNA that can regulate gene expression and participate in the regulation of myogenesis. However, the molecular mechanisms and potential roles of circRNAs in bovine muscle development remain largely unknown. Nevertheless, the RNA splicing factors regulating the biogenesis of bovine circRNA have not yet been characterized. In this study, we identified a novel circRNA, circMEF2D, formed by back-splicing of constitutive exons (exons 5-7) of the bovine MEF2D gene. Functional assays showed that circMEF2D inhibited the proliferation and differentiation of bovine myoblasts. Importantly, we showed that circMEF2D regulated the PI3K-AKT signaling pathway through direct and competitive binding to miR-486. Furthermore, to explore the formation mechanism of circMEF2D, we explored the MEF2D gene alternative splicing progress. Four alternative linear variants of MEF2D were found. Due to its role in alternative splicing, the RNA-binding protein HNRNPA1 was selected for further study and the modulation of HNRNPA1 levels showed that it negatively regulated both back-splicing and linear splicing of MEF2D gene. Overall, in addition to the characterization of bovine circRNAs, these findings revealed the crucial role of HNRNPA1 in MEF2D gene alternative splicing and demonstrated a regulatory circMEF2D-miR-486-PI3K-AKT axis.