Search Results (329)

Insulin-like growth factor 2 (IGF2) plays a pivotal role in regulating growth and development; however, its functional involvement in skeletal muscle satellite cells (SMSCs) remains incompletely understood. To elucidate the regulatory role of IGF2, goose SMSCs were engineered to overexpress IGF2 via lentiviral transduction, followed by comprehensive transcriptomic profiling. Comparative analysis revealed 2802 differentially expressed genes (DEGs) in IGF2-overexpressing cells relative to controls, comprising 1202 upregulated and 1600 downregulated genes. IGF2 overexpression markedly activated fibrogenic programs, as evidenced by the upregulation of AP-1 complex components (FOS, JUN), extracellular matrix-related genes (COL1A1, COL5A3), and Wnt signaling receptors (FZD1, FZD7). In contrast, genes involved in myogenic differentiation and contractile function were broadly suppressed, including key myogenic transcription factors (MEF2C, MEF2D), sarcomeric structural proteins (MYBPC1, ACTN2, MYOM3), and metabolic enzymes. Through the construction of protein–protein interaction networks coupled with functional enrichment analysis, we observed a concerted suppression of myogenic regulatory networks critical for myofiber formation. Quantitative real-time PCR validation further confirmed the reliability of the transcriptomic data. Collectively, these findings suggest that overexpression of IGF2 induces a phenotypic shift from myoblasts toward a fibroblast-like state, uncoupling proliferation from differentiation while enhancing fibrogenic identity. This study provides novel insights into IGF2-mediated regulatory mechanisms underlying skeletal muscle development and fibrotic processes. Full article

This study investigated the synergistic effects of liquid fermentation of rapeseed meal (RSM) on feed microbiota, growth performance, and muscle development in growing pigs. RSM was fermented using four compound probiotics and eleven enzyme preparations, and microbial changes were analyzed using 16S rRNA sequencing. Seventy-two Duroc × Jingfen White pigs were randomly assigned to three groups: soybean meal (Ctrl), RSM, and fermented RSM (FRSM). FRSM showed higher trichloroacetic acid-soluble protein (TCA-sp) content and significantly lower neutral detergent fiber (NDF), acid detergent fiber (ADF), anti-nutritional factors (ANFs), and toxins (TS) (p < 0.01). Fermentation increased microbial diversity, with higher abundances of Lactobacillus and Pediococcus. Compared with Ctrl and RSM, the feed-to-gain ratio (F/G) decreased in the FRSM group (p < 0.01). FRSM also improved serum antioxidant capacity, enhanced intestinal villus height (VH)and villus height/crypt depth ratio (VH/CD), and upregulated the expression of tight junction proteins (ZO-1, occludin) and the anti-inflammatory factor IL-10 (p < 0.01). FRSM group also increased myofiber diameter and cross-sectional area in the longissimus dorsi and elevated MyoD, MyoG and Myf5 expression (p < 0.01). RNA-seq revealed 2094 differentially expressed genes enriched in metabolic pathways. Overall, FRSM improved growth performance, intestinal health, and muscle development in growing pigs, which may guide the development of protein resource utilization technologies. Full article

CLN1 disease, caused by mutations in the PPT1 gene, is a fatal neurodegenerative lysosomal storage disorder. While central nervous system (CNS) pathology is well documented, the impact on peripheral tissues remains unclear. Having previously described severe spinal cord pathology, we investigated whether PPT1 deficiency also impacts the neuromuscular junction (NMJ) and skeletal muscle, and whether early systemic gene therapy can prevent these disease manifestations. NMJ morphology, terminal Schwann cell (tSC) coverage, and skeletal muscle structure were examined in symptomatic and end-stage Ppt1^−/− mice. Neonatal mice received systemic AAV9-hCLN1 gene therapy via intravenous injection. Untreated Ppt1^−/− mice exhibited pronounced NMJ pathology, including progressive tSC loss, apparently reduced innervation, and increased abnormal acetylcholine receptor clustering. In parallel, we observed skeletal muscle atrophy, with decreased myofiber diameter and reduced myonuclear content, despite preserved sciatic nerve morphology. Systemic AAV9-hCLN1 therapy partially prevented or ameliorated these phenotypes, preserving NMJ innervation and muscle fiber structure. These findings identify peripheral NMJ and muscle abnormalities as previously unrecognized features of CLN1 disease and provide proof-of-concept that early systemic gene therapy can mitigate these effects. Our results highlight the systemic nature of CLN1 pathology and support the need for treatments that address both CNS and peripheral targets for comprehensive disease modification. Full article

Skeletal muscle myopathy remains a significant cause of disability with limited treatment strategies. Advancements in tissue engineering have led to the development of borophosphate bioactive glasses (BPBGs) capable of enhancing skeletal muscle structure and function. Using a mouse model of severe myopathy (D2.mdx), we investigated muscle force, regeneration, angiogenesis and inflammation at 14, 70 and 140 days post-treatment (dpt). Tibialis anterior (TA) muscles of D2.mdx mice that received a single injection of cobalt oxide-doped BPBG (CoO-TRIM) particles exhibit greater active force, myofiber size, and regeneration through 70 dpt compared to control D2.mdx mice injected with Saline. Vascular endothelial growth factor (VEGF) was elevated up to 70 dpt in D2.mdx CoO-TRIM mice followed by increased muscle vascularity. As a marker of inflammation, interleukin (IL)-6 increased in D2.mdx CoO-TRIM mice compared to D2.mdx Saline controls at 14 dpt, with no differences at 70 or 140 dpt. No differences were observed in outcome measures between wild-type (WT) CoO-TRIM mice and WT Saline controls. We report that CoO-TRIM can stimulate VEGF production and promote restoration of muscle structure and function when inflammation is present. Local injection of an inorganic biomaterial alone can benefit myopathic skeletal muscle. Full article

Hypoxia is a common environmental stress in nature and aquaculture, but the adaptation mechanisms of flatfish to chronic hypoxia and its effects on flesh quality remain unclear. In this study, the turbot was cultured at control normoxia (CON, 6.5 ± 0.5 mg/L) or chronic hypoxia (CHO, 3.5 ± 0.5 mg/L) for 8 weeks; then, the growth, energy metabolism, meat quality, and the expression of related genes were measured. The CHO group significantly reduced the digestibility (p < 0.05), weight gain (p < 0.001), and body indexes (p < 0.01), but increased feed conversion ratio (p < 0.001) in turbot. Meanwhile, the CHO group decreased muscle texture, total amino acid, soluble protein (p < 0.001), glycogen contents, and myofiber numbers (p < 0.001), while increasing myofiber diameters and lactate content (p < 0.01). In addition, chronic hypoxia increased the hepatic angiogenesis by activating the hif1α/vegfa pathway (p < 0.05) and decreased the whole fish lipid content and liver n-3 polyunsaturated fatty acid levels (p < 0.05). In summary, chronic hypoxia reduced the growth, nutrient content, and flesh quality of turbot. This study provides important references for elucidating the adaptation mechanisms of flatfish to chronic hypoxia and for developing mitigation strategies. Full article

Background/Objectives: Dynamic changes in inorganic phosphate (Pi), phosphocreatine (PCr), and pH during post-exercise recovery reflect underlying muscle energetics and mitochondrial ATP synthesis, but the conventional single-pool model assuming uniform metabolic response fails to address myofiber composition and pH-dependent metabolic heterogeneity in skeletal muscle. This study aimed to characterize the interplay between pH, Pi, and PCr, and to develop an analytical method for assessing pH-resolved ATP synthesis using ³¹P MRS. Methods: Five healthy subjects underwent dynamic ³¹P MRS scans during plantar flexion exercise. ATP synthesis was evaluated from post-exercise PCr and Pi recovery time courses using the single-pool model, and from Pi recovery time courses using a multi-pool model in which the Pi signal lineshape was segmented into four pH-specific pools: alkaline (pH 7.3 ± 0.2), neutral (pH 7.0 ± 0.1), mildly acidic (pH 6.8 ± 0.1), and moderately acidic (pH 6.6 ± 0.1). Results: The single-pool model showed that during exercise, Pi increased proportionally to PCr depletion, and both Pi and PCr recovered monoexponentially immediately after exercise with ${\tau }_{\mathrm{Pi}} \left(33\pm 9 \mathrm{s}\right)<{\tau }_{\mathrm{PCr}} (40 \pm 9 \mathrm{s})$; ATP remained stable while pH exhibited a “heart-beat” pattern, characterized by an initial alkalization followed by neutralization during exercise, a post-exercise acidic undershoot, and a subsequent slow recovery (${\tau }_{\mathrm{pH}}\gg {\tau }_{\mathrm{PCr}}$). The four-pool model demonstrated a pronounced pH dependence of Pi recovery, with slower recovery at lower pH (${\tau }_{\mathrm{Pi}}$: 19 ± 6 s at pH 7.3, 25 ± 7 s at pH 7.0, 32 ± 11 s at pH 6.8, and 46 ± 17 s at pH 6.6). Pi recovery is slowed with aging under acidic conditions, with little or no effect observed at neutral or alkaline pH. These results provide new insights into skeletal muscle metabolic heterogeneity, reflecting how different myofiber microenvironments modulate ATP synthesis. Conclusions: By overcoming the constraints of the single-pool model, the proposed multi-pool framework uncovers pH-dependent ATP synthesis and provides direct evidence of pronounced metabolic heterogeneity in skeletal muscle during exercise and recovery. Full article

Regenerative rehabilitation can enhance skeletal muscle recovery following trauma-induced volumetric muscle loss (VML). We previously optimized fibrin-laminin hydrogels for muscle regeneration and an electrically stimulated eccentric contraction training (EST) for muscle rehabilitation. The goal of this study was to examine the combined effect of these two therapies on maximizing tissue recovery. A VML defect was created by removing ~20% of muscle mass from the tibialis anterior (TA) muscle in adult male Lewis rats. The injured TA muscles were treated with fibrin-laminin (FBN450) hydrogel. EST was implemented 2 weeks post-injury at both 100 Hz and 150 Hz frequencies and continued for 4 weeks. The results showed no improvement in muscle mass or function with combined FBN450 and EST application. Histological analysis revealed significantly reduced type 2B myofiber cross-sectional area (CSA) and percentage in the combined hydrogel and EST treatment group. Gene expression studies showed >20-fold higher inflammatory (e.g., CCR7, CD163) and fibrotic (e.g., Col1a1) signaling, with no concomitant increase in myogenic markers in the hydrogel + EST group. Collectively, these results indicate that the FBN450 hydrogel therapy did not synergize with EST to improve outcomes following VML. Full article

Background/Objectives: Cancer cachexia involves progressive skeletal muscle and adipose tissue loss, which is further aggravated by cisplatin chemotherapy via increased systemic inflammation, tissue catabolism, and renal toxicity. The present study aimed to evaluate whether a combination of amaranth protein hydrolysate and Agastache rugosa extract (AKE) could attenuate cisplatin-associated cachexia and nephrotoxicity in CT26 tumor-bearing mice. Methods: Cancer cachexia was induced by subcutaneous CT26 cell inoculation in 6-week-old male BALB/c mice, followed by a 7-day tumor establishment period. Cisplatin was then administered intraperitoneally, and AKE (125 or 250 mg/kg/day) was given daily by oral gavage for 14 days. Results: AKE administration significantly alleviated cisplatin-induced body weight loss and systemic inflammation, accompanied by preservation of skeletal muscle and adipose tissue mass, as well as increased myofiber cross-sectional area and adipocyte size. AKE markedly reduced serum inflammatory cytokines, blood urea nitrogen, and creatinine levels, indicating protection against cisplatin-induced renal injury. Mechanistically, AKE suppressed renal apoptosis through inhibition of mitogen-activated protein kinase signaling. In skeletal muscle, AKE attenuated muscle atrophy by modulating protein turnover pathways, including downregulation of muscle-specific ubiquitin ligases and restoration of Akt/mTOR and FoxO3a signaling. Furthermore, AKE mitigated adipose tissue wasting by suppressing AMP-activated protein kinase-dependent browning and restoring adipogenic signaling involved in lipid storage and differentiation. Conclusions: These findings demonstrate that AKE confers comprehensive protection against cisplatin-induced cachexia and nephrotoxicity by coordinately preserving muscle and adipose tissue and attenuating renal injury, suggesting its potential as a functional nutritional strategy to alleviate chemotherapy-associated tissue wasting. Full article

Diabetes mellitus severely impairs skeletal muscle regeneration after injury, limiting satellite cell activation and angiogenesis and disrupting barrier integrity while increasing fibrosis. Hypobaric hypoxia has been proposed to improve the regenerative microenvironment through hypoxia-responsive signaling, but its temporal effects and the coordination between vascular and myogenic programs in diabetic muscle remain unclear. To clarify these processes, adult male mice were divided into five groups: diabetes mellitus control (DM), cardiotoxin-injured (CTX) diabetes assessed on days 7 and 14 (CTX7, CTX14), and hypobaric-hypoxia-treated diabetic injury assessed on days 7 and 14 (H+CTX7, H+CTX14). Animals in the hypoxia groups were exposed to a hypobaric hypoxia chamber for 8 h per day for 14 days. Fibrosis, angiogenic and myogenic markers, and endothelial junctional genes were examined using histology, immunofluorescence, immunoblotting, and qRT-PCR (Quantitative Real-Time PCR). Hypobaric hypoxia on day 7 enhanced HIF-1α (hypoxia-inducible factor 1 alpha), VEGF (vascular endothelial growth factor), eNOS (endothelial nitric oxide synthas), Kdr (kinase insert domain receptor, VEGFR-2), and Angpt2 (angiopoietin-2) expression, accompanied by simultaneous endothelial sprouting and early myogenic stimulation compared to CTX7. Improvements were observed in Angpt1 (angiopoietin-1), Cdh5 (cadherin-5, VE-cadherin), Emcn (endomucin), the Angpt1/Angpt2 ratio, and CD31 density. Myogenin and MyHC (myosin heavy chain) were induced with a reduction in eMyHC (embryonic myosin heavy chain) in accordance with stabilization of endothelium and maturation of fibers, which occurred by day 14. A decrease in fibrosis and an increase in the myofiber cross-sectional area occurred. These findings suggest that hypobaric hypoxia modulates HIF-1α signaling, which in turn induces the VEGF-Kdr-eNOS pathway and the angiopoietin–Tie2–VE-cadherin pathway. Together, these pathways coordinate vascular remodeling and myogenic regeneration, ultimately improving the structural and functional recovery of diabetic muscle. Full article

Introduction: We previously showed that baboon offspring born to mothers deprived of estrogen during the second half of gestation exhibited insulin resistance prior to and after the onset of puberty. Moreover, the size of skeletal muscle myofibers and the number of microvessels important for delivery of insulin/glucose to myofibers were lower in near-term fetuses deprived of estrogen during pregnancy, and myofiber capillarization remained reduced in post-pubertal offspring deprived of estrogen in utero. However, it remains to be determined whether skeletal muscle size is restored to normal in animals deprived of estrogen in utero after the onset of puberty/gonadal estrogen production. Methods: To answer this question, the current study quantified the size and number of slow and fast fibers in biopsies of vastus lateralis skeletal muscle obtained from post-pubertal female baboon offspring 9–12 years old, born to mothers who were untreated (n = 7) or treated during the second half of gestation with letrozole (n = 6; suppressed maternal and fetal estrogen by >90%) or letrozole plus estradiol benzoate (n = 3). Results: Results indicated that skeletal muscle slow and fast fiber growth in female offspring appeared to occur by hypertrophy and that respective size of fibers after the onset of puberty was similar in offspring born to mothers who were untreated or deprived of estrogen in utero. Conclusions: Postnatal myofiber hypertrophy likely reflects the impact of the pubertal surge in and continued exposure of offspring myofibers to ovarian estrogen and is restored to normal in post-pubertal female offspring deprived of estrogen in utero. Full article

Myopathy encompasses a group of diseases characterized by abnormalities in both muscle function and structure. However, the underlying regulatory mechanisms of newly formed myofiber development remain poorly defined. No promising therapeutic approach has been developed, but numerous medication options are available to alleviate symptoms. Our previous studies demonstrated that adenosine kinase (ADK) is critical in regulating adenosine metabolism, pathological angiogenesis, pathological vascular remodeling, and vascular inflammatory diseases. Adenosine dynamically distributes between extracellular and intracellular, and adenosine concentration regulates ADK expression. However, the mechanism by which adenosine triggers an ADK-dependent intracellular signaling pathway to regulate skeletal muscle regeneration is not well defined. This study aimed to evaluate whether the adenosine-induced intracellular signaling pathway is involved in regulating myopathy, and how it regulates the development of newly formed myofibers. In this study, an intramuscular injection of cardiotoxin was used to induce a skeletal muscle injury model; satellite cells and C2C12 cells were employed. Whether adenosine regulates satellite cell activity, new myofiber formation and differentiation, as well as fusion of myofibers, were determined by H&E staining, BrdU incorporation assay, and spheroid sprouting assay. Interaction between ADK and PFKFB3 was evaluated by IF staining, PPI network analysis, molecular docking simulation, and CO-immunoprecipitation assay. The results demonstrated that adenosine dynamically distributes between extracellular and intracellular through concentrative nucleoside transports or equilibrative nucleoside transporters, and it rapidly induces an ADK-dependent intracellular signaling pathway, which interacts with PFKFB3-mediated glycolytic metabolism to promote satellite cell activity, new myofiber formation, differentiation, and fusion, and eventually enhances skeletal muscle regeneration after injury stress. The remarkable endogenous regeneration capacity of skeletal muscle, which is regulated by adenosine-triggered intracellular signaling, presents a promising therapeutic strategy for treating muscle trauma and muscular dystrophies. Full article

The role of LAP proteins expressed in skeletal muscles (ERBIN, LANO, and SCRIBBLE) and at neuromuscular junctions (NMJs) remains largely unknown. Our previous data demonstrate that LAP proteins are differentially expressed in muscle cells, nerve endings, and terminal Schwann cells, though they are all expressed in myofibers and accumulate at NMJs. ERBIN and SCRIBBLE align with acetylcholine receptor clusters (CHRNs) at the NMJ. In vivo ablation of Erbin is associated with smaller CHRN and upregulation of Lano and Scribble. However, SCRIBBLE was also shown to influence the fate decision of muscle stem cells. Here, we investigated how the absence of SCRIBBLE in skeletal muscle cells might impair skeletal muscle fibers or NMJs. Although conditional Scribble knockout mice did not exhibit changes in weight or viability, force per weight decreased slightly. This was supported by compromised neuromuscular transmission and increased NMJ fragmentation. Moreover, Scribble knockout muscles transcribe less myosin heavy chain genes. Here, we also showed that RAB5, an effector of endocytic recycling, interacts with all LAP proteins, but in Scribble knockout muscles, reduced interaction was detected with ERBIN and LANO. These data suggest that a delicate signaling network employing LAP proteins is necessary for skeletal muscle fibers and NMJs. Full article

This study investigated muscle quality differences between wild-type (WT) and yellow-mutant (YM) Triplophysa siluroides. Texture analysis showed WT T. siluroides had significantly greater hardness, gumminess, and resilience than YM. Histological and biochemical analyses ruled out myofiber diameter/density as drivers, instead identifying reduced collagen in YM as key, as confirmed by Picrosirius red staining, collagen quantification, and transmission electron microscopy. Transcriptomic and proteomic analyses revealed that TGF-β/BMP pathway suppression in YM resulted in downregulation of core molecules (e.g., BMP2 and SMAD1), collagen-related genes (e.g., COL1A1a and COL1A1b), and ECM-related genes (e.g., TNC and FN1), potentially influencing collagen synthesis and ECM homeostasis. Notably, melanin gene TYRP1 was also downregulated in YM T. siluroides, suggesting a link between pathway suppression, muscle quality alteration, and body pigmentation. The potential role of the BMP2-SMAD1-TYRP1 axis in the association between muscle quality and body colour provides novel mechanistic insights, offering molecular targets for the breeding of T. siluroides with superior commercial traits. Full article

Background/Objectives: This paper provides a review of the literature data concerning the cellular and molecular mechanisms of heart failure and sudden cardiac death in hypertrophic cardiomyopathy (HCM), and explores approaches used for their pathogenetic correction. Methods: This study highlights genetically determined targets of primary damage to the cardiomyocyte ultra-structure—the actomyosin complex of sarcomeres and mitochondria. Results/Conclusions: Damage to these structures leads to heart failure and an increased risk of sudden cardiac death, manifesting against a background of phenotypic features such as cardiac remodeling, asymmetric hypertrophy, left ventricular outflow tract obstruction, myofiber disarray, and atrial fibrillation. Both invasive and non-invasive approaches for the pathogenetic management of these fatal complications are characterized. Full article

Background/Objectives: Premature births below 32 weeks of gestation generally require respiratory oxygen support, leading to a relatively hyperoxic environment compared to in utero conditions. Transient hyperoxia exposure has been linked to an elevated risk of chronic lung disease and retinopathy of prematurity; however, its effects on skeletal muscles remain elusive. This study aimed to investigate the effects of hyperoxic exposure in rats as a model of premature infants receiving supplemental oxygen (30–60% O₂ for several weeks). We hypothesized that rats exposed to postnatal hyperoxia would exhibit muscle fiber atrophy and alterations in fiber type. Methods: We used a rat model in which newborns were exposed to 80% oxygen from birth until postnatal day 12. We assessed the gastrocnemius muscles of rat legs at 12 weeks. Results: Rats exposed to hyperoxia showed substantially increased protein expression of Atrogin-1, along with elevated levels of adipophilin, myogenic differentiation factor 1, and myogenin. No significant changes were observed in the expression of slow or fast myosin heavy chain proteins. However, myofiber size in the gastrocnemius muscle was reduced in the hyperoxia-exposed group compared to the control group. Conclusions: Thus, transient hyperoxia exposure during early life can impede skeletal muscle development, potentially extending into adulthood. Full article