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Defective transcription of AAGAG satellite DNA causes sex-ratio meiotic drive in Drosophila.

Tomohiro Kumon, Mami Nakamizo-Dojo, Amelie A Raz +3 more

Male germ cells have complex transcriptomes, with a large fraction of the genome being transcribed. This includes protein-coding genes (often not translated), non-coding DNA, and repetitive DNA, such as transposons and satellite DNA, which are normally silenced as heterochromatin. The significance of such widespread transcription remains unknown. Here, we show that a heterochromatin protein, HP2, is required for the transcription of AAGAG satellite DNA in Drosophila spermatocytes. HP2 depletion leads to abnormal retention of heterochromatin histone marks (H3K9me3) and spermatid death during sperm DNA packaging, leading to a model that transcription of AAGAG satellite DNA facilitates the remodeling of its heterochromatic nature in preparation for sperm DNA packaging. Strikingly, the severity of the spermatid death correlates with the amount of AAGAG satellite DNA carried by the spermatids, leading to preferential death of Y chromosome-containing spermatids over X-containing spermatids, and hence sex-ratio meiotic drive phenotype. We propose that widespread spermatocyte transcription may reflect the process of chromatin remodeling to allow sperm DNA packaging. We further propose that differential composition and amount of satellite DNA on chromosomes may underlie naturally occurring male meiotic drive.

Haplotype-resolved centromeric chromatin organization from a complete diploid human genome.

Yuan Xu, Hailey Loucks, Julian Menendez +23 more

Centromeres ensure proper chromosome segregation during cell division, yet the organization and regulation of centromeric chromatin within satellite DNA arrays remain incompletely understood. Here, we leverage the complete diploid human genome benchmark (T2T-HG002) to provide a detailed study of centromeric sequence and chromatin architecture on individual haplotypes. Using adaptive-sampling-enriched, ultra-long-read DiMeLo-seq, we achieve single-molecule chromatin profiling across all centromeres, revealing that along single chromatin fibers, CENP-A, the histone variant specifying centromere identity, forms multiple discrete subdomains within hypomethylated centromere dip regions (CDRs) that are flanked by H3K9me3-enriched heterochromatin. Despite underlying sequence variation, CDRs localize to sequence-homogeneous domains and maintain relatively balanced CENP-A dosage and aggregate length across all chromosomes and between haplotypes. Further, we show that bidirectional changes to centromeric and pericentromeric DNA methylation are accompanied by changes to centromeric chromatin architecture. In passaged cells with centromeric hypomethylation, subdomain boundaries are eroded, and adjacent CENP-A domains tend to merge and expand. Conversely, in pluripotent stem cells with centromeric hypermethylation, CDRs are fundamentally reorganized, such that discrete hypomethylated domains are frequently consolidated into broader contiguous tracts. These methylation-associated CDR restructuring events suggest that DNA methylation acts as a principal regulator of human centromere organization, with implications for understanding centromere plasticity, epigenetic inheritance, and chromosomal instability in development and disease.

Preoperative systemic inflammation and muscle fatty infiltration are prognostic factors for quadriceps atrophy following anterior cruciate ligament reconstruction.

Hanyi Wang, Yuqi Li, Hao Zheng +5 more

Muscle atrophy following anterior cruciate ligament reconstruction (ACLR) significantly impedes functional recovery, yet its underlying prognostic factors and potential cellular mechanisms remain poorly understood.

EXPRESS: CXCL12/CXCR4 Axis in Neuropathic Pain: Insights from Preclinical Models and Translational Implications.

Ming Li, Xiao-Xiao Lu, Lu-Yao Cai +2 more

Neuropathic pain affects approximately 7%-10% of the global population, significantly impairing patients' quality of life and placing a substantial burden on public health systems. Current pharmacological treatments have limited efficacy and are often accompanied by notable side effects, highlighting the urgent need for novel therapeutic targets. Increasing evidence supports the important role of chemokines and their receptors in neuro-immune interactions underlying pain sensitization. Among these pathways, the CXCL12/CXCR4 axis has emerged as an important regulator of both the initiation and maintenance of neuropathic pain. Beyond its canonical function in immune cell trafficking, the CXCL12/CXCR4 axis modulates neuronal excitability, glial activation, synaptic plasticity, and nociceptive sensitization. Notably, this axis is frequently upregulated in both peripheral and central neurons, as well as in multiple glial populations, including astrocytes, microglia, and satellite glial cells, across diverse neuropathic pain models. Importantly, CXCR4 is one of the few chemokine receptors with a clinically approved antagonist, highlighting its unique translational potential. This review systematically summarizes the expression patterns, biological functions, and pain-related mechanisms of the CXCL12/CXCR4 axis in preclinical models of neuropathic pain and discusses current limitations and potential future therapeutic strategies targeting this pathway.

Dual roles of syndecan-4 in regulating chicken fibrosis in vitro.

Lucie Pejšková, Nina Therese Solberg, Marianne Lunde +3 more

Wooden Breast (WB) is a myopathy affecting the skeletal breast muscle (Pectoralis major) in broiler chickens and is characterized by muscle fiber damage and varying degrees of fibrosis, ECM remodeling and inflammation. Several key factors such as pro-inflammatory cytokines like TGF-β1 and IL-1β, drive fibrosis in WB myopathy. We have previously shown that the expression of syndecan-4 (SDC4), a transmembrane proteoglycan, was increased in WB poultry skeletal muscle tissue. Furthermore, the ectodomain shedding of SDC4 by matrix metalloproteinases (MMPs) differed in the skeletal muscle satellite cells from isolated affected chickens compared with normal. While SDC4 has been previously implicated as a key driver for regulating myofibroblast activity in mechanically induced fibrosis in cardiac tissue, its specific role and shedding activity in chicken fibroblasts in relation to WB myopathy remain poorly understood.

DNA O-MAP uncovers the molecular neighborhoods associated with specific genomic loci.

Yuzhen Liu, Christopher D McGann, Conor P Herlihy +14 more

The accuracy of crucial nuclear processes such as transcription, replication, and repair depends on the local composition of chromatin and the regulatory proteins that reside there. Understanding these DNA-protein interactions at the level of specific genomic loci has remained challenging due to technical limitations. Here, we introduce a method termed 'DNA O-MAP', which uses programmable peroxidase-conjugated oligonucleotide probes to biotinylate nearby proteins. We show that DNA O-MAP can be coupled with label-free or sample multiplexed quantitative proteomics, targeted chemical perturbations, and next-generation sequencing to quantify DNA-proximal proteins and DNA-DNA interactions at specific genomic loci in human and murine cells. Furthermore, we establish that DNA O-MAP is applicable to both repetitive and unique genomic loci of varying sizes, from kilobase HOX gene clusters to megabase alpha-satellite repeats, and that DNA O-MAP can measure proximal molecular effectors in a homolog-specific manner.

Mitochondrial transfer as a therapeutic target for peripheral neuropathy.

Junlin Wei, Fang Wang

Satellite glial cells transfer mitochondria to sensory neurons via myosin 10-dependent tunneling nanotubes. Ji et al. show that this transfer is impaired in diabetic neuropathy, causing energy failure. Restoring it via cell or mitochondrial transplantation alleviates pain and promotes nerve regeneration, revealing a new therapeutic strategy for peripheral neuropathy.

Plant-derived exosome-like vesicles enhance exercise-induced muscle recovery and sleep quality.

Emrah Aykora, Damla Aykora

Exercise-induced muscular stress triggers a complex cascade of adaptive responses, including micro-injury, inflammation, activation of satellite cells, mitochondrial remodeling, and myofibrillar repair. The efficiency of recovery processes is crucial for athletic performance, especially among elite athletes, where rapid restoration of muscle function, reduction of inflammation, and improved sleep quality influence training results. Beyond traditional recovery methods, EVs and, more recently, plant-derived exosome-like nanovesicles (PELNs) have emerged as promising bioactive mediators of intercellular communication and tissue regeneration. PELNs contain various biomolecules such as lipids, proteins, small RNAs, and plant-specific metabolites that may affect oxidative stress, inflammatory signaling, and cellular repair pathways. While most research has focused on mammalian or cell-line sources, growing evidence indicates that PELNs may improve muscle regeneration and recovery through cellular modulation and enhanced sleep-related recovery. Notably, PELNs represent a multi-target strategy that may simultaneously modulate neuroendocrine pathways involved in sleep regulation and metabolic-inflammatory mechanisms governing skeletal muscle repair. By influencing circadian rhythm signaling, mitochondrial dynamics, and redox homeostasis, PELNs may bridge the sleep-muscle recovery axis, an emerging concept in exercise physiology. This dual regulatory capacity distinguishes PELNs from conventional recovery interventions and highlights their innovative and translational potential in sports science. This review aims to compile current evidence linking PELNs to exercise-induced muscle recovery, highlighting potential mechanisms, including the regulation of inflammatory and redox balance, microRNA-driven signaling, and neurometabolic adaptation. By combining insights from exercise physiology and molecular regenerative biology, we propose that PELNs offer a natural approach to enhancing recovery and performance in athletes.

Centriolar satellites regulate CEP350 mRNA localization and centrosome amplification.

Abraham Martinez, Chad G Pearson

Messenger RNAs (mRNAs) accumulate at centrosomes in mitosis and interphase, yet the mechanisms governing their localization and the functional significance of centrosomal localization remain poorly understood. Here, we investigate the regulation and function of the centrosome-localized mRNA, CEP350 . We find that CEP350 mRNA localizes to centrosomes during S phase via the centriolar satellite protein CEP131 and the RNA binding protein (RBP) Unkempt (UNK), in a microtubule (MT)-dependent manner. CEP131 and UNK stabilize CEP350 mRNA to maintain CEP350 mRNA steady-state levels. Furthermore, CEP131 and UNK promote normal CEP350 protein levels at centrosomes. CEP350 is required for PLK4-induced centriole overduplication but is less important for canonical centriole duplication. Moreover, CEP131, UNK, and CEP350 are important for centrosome amplification in triple-negative breast cancer cells. Together, these findings reveal a centriolar satellite-RBP pathway regulating CEP350 mRNA localization to centrosomes.

TRPV2 is essential for calcium signalling in the early stages of myogenesis.

Yanzhu Chen, Kimiaki Katanosaka, Yuki Katanosaka

Skeletal muscle responds to stressors such as exercise and muscle injury by adaptive remodelling. The resilience of skeletal muscle involves not only mature muscle fibres but also the adjacent muscle satellite cells (MuSCs). We previously found that transient receptor potential vanilloid type 2 (TRPV2) is expressed in MuSCs and is essential for MuSC proliferation and activation in MuSC-specific conditional knockout mice. These mice show no mechanical-load-induced muscle hypertrophy and delayed injury-induced muscle regeneration. The effect of TRPV2 on Ca2+ signalling during early myogenesis is unknown; however, here, we demonstrate that tranilast, an inhibitor of TRPV2, suppressed IP3R-derived Ca2+ oscillations in early myogenesis. The addition of adenovirus (Ad)-TRPV2 or Ad-Cre recombinase to floxed-TRPV2 cells modulated TRPV2 expression, and demonstrated the TRPV2 dependence of IP3R and MEF2c expression, nuclear translocation of MEF2c, and Ca2+ oscillations. These findings indicate that TRPV2 regulates intracellular Ca2+ signalling during early myogenesis and highlight its potential as a target for the prevention and treatment of muscle disorders.

Self-assembled mesoporous bioglass polyphenol nanozymes for repairing musculoskeletal trauma.

Shuao Zhao, Yesheng Jin, Zhihao Jia +7 more

Volumetric Musculoskeletal Trauma (VMST), which is characterized by volumetric muscle loss accompanied by bone injury, poses a significant challenge to regenerative medicine. While current therapies primarily focus on the individual regeneration of muscle or bone, there is no systematic and integrated treatment strategy. In this study, we developed a CuMBG-PA, a copper-doped nanozyme based on mesoporous bioactive glass (MBG) and procyanidin (PA), for integrated muscle and bone repair of VMST. CuMBG-PA self-assembles into a stable polyphenol network via Cu-PA coordination bonds, enhancing PA stability and reactive oxygen species-scavenging capacity. In vitro and in vivo experiments demonstrated that CuMBG-PA promoted osteogenesis and myogenesis while exhibiting high biocompatibility and antibacterial activity. Single-cell RNA-sequencing results revealed that CuMBG-PA synergistically induces stem cell differentiation and promotes tissue repair through multiple myoskeletal shared metabolic pathways. Mechanistically, CuMBG-PA exerts its beneficial effects by increasing the number of Proteoglycan 4 (Prg4) + fibro/adipogenic progenitor cells (FAPs), which highly express fibronectin and insulin-like growth factor. In addition, PRG4 regulates immune cells, removes overactivated muscle satellite cells, reduces muscle fibrosis, and promotes functional recovery during regeneration. In summary, this work demonstrates that the novel self-assembled CuMBG-PA nanozyme represents a potential biomaterial-based strategy for integrated muscle and bone repair in VMST.

snRNA sequencing-based skeletal muscle analysis of Jiangquan black pigs with different average daily growth rates.

Hongzhen Cao, Jing Wang, Yunzhou Wang +7 more

The Jiangquan black pigs, a new breed of swine obtained by introducing traits from Duroc pigs into Yimeng black pigs, exhibits fast growth rates and high meat quality. To understand how daily weight gain influences muscle development in this breed, we analyzed longissimus dorsi muscle cell subpopulations from Jiangquan black pigs using snRNA and bulk RNA sequencing. Thirteen distinct cell types (e.g., muscle stem cells, satellite cells, fibroblasts) were identified, and marker genes (PAX7, MYOD, MYOG) were found to exhibit stage-specific expression during differentiation. Pseudotime analysis revealed the differentiation trajectories of these cell populations, while cell cycle analysis uncovered the higher mitotic activity in satellite cells of the fast-growth versus slow-growth groups. Furthermore, cell communication analysis highlighted the interactions between muscle cells and other cell types. Finally, intergroup analysis revealed that 2,466 and 2,597 genes were differentially expressed in muscle stem cells and muscle satellite cells, respectively. These genes were enriched in disease-related pathways. This study provides a single-cell resolution atlas of porcine muscle development, offering insights into the genetic regulation of growth and potential targets for breeding optimization.

Telocytes in skeletal muscle: Emerging players in homeostasis and repair/regeneration.

Irene Rosa, Eloisa Romano, Mirko Manetti

Telocytes (TCs) have recently emerged as novel components of the skeletal muscle interstitium. They are distinguished from other stromal cells by their immunophenotypic profiles and, especially, unique ultrastructural traits. Specifically, TCs feature a small cell body and very long, thin telopodes with a moniliform appearance conferred by the alternation of slender segments (podomers) and small dilated portions (podoms). Experimental evidence suggests that, as part of the skeletal muscle stem cell niche, TCs may be involved in orchestrating satellite cell activation and myogenic differentiation through both direct physical interactions and paracrine signaling. Yet, further in-depth research is needed to uncover specific immunophenotypic signatures for skeletal muscle TCs within the niche, as well as to identify the signaling pathways by which they influence neighboring satellite cells and, possibly, other cellular components of the niche. In the present review, particular emphasis is placed on the putative strategic role of TCs in maintaining skeletal muscle tissue homeostasis, their involvement in muscle pathological alterations, and, most importantly, their possible role in the coordination of the regenerative response following injury. In perspective, the promising therapeutic potential of TC-based strategies to enhance skeletal muscle tissue repair/regeneration and restrain post-injury fibrosis is also discussed.

The Crucial Role of Exercise in Promoting Adolescent Muscle Development.

Xilong Hu, Haiwang Shi, Rui Duan

Skeletal muscle, as one of the largest organ system in the human body, exerts a determining influence on adolescents' mastery of motor skills and their lifelong health. Puberty represents a critical window for muscle development, during which the quality of myogenesis not only shapes athletic potential but also profoundly influences long-term health outcomes in adulthood. Under pathological conditions, such as obesity, an aberrant metabolic environment can compromise muscle function in youth, impede the progression of motor abilities, and increase susceptibility to metabolic disorders. It is well established that scientifically prescribed exercise interventions effectively unlock adolescents' muscle-building potential, thereby laying a solid foundation for enduring physical performance and overall well-being.This chapter offers a systematic overview of the key biological principles that regulate skeletal muscle development during puberty and provides an in-depth analysis of the mechanisms and signaling pathways by which structured exercise drives muscle growth and functional adaptation. In addition, it examines the challenges posed by muscle structural and functional impairments under pathological states and evaluates how targeted exercise regimens can restore and enhance muscle health. By mastering the conceptual framework presented here, coaches and parents will be better equipped to identify early warning signs of impaired muscle development, support individualized training plans that optimize motor skill acquisition while minimizing injury risk, and implement proactive interventions to prevent metabolic dysregulation and age-related muscle decline.

Global, regional and national burden of ischemic heart disease attributable to suboptimal diet, 1990-2023: a Global Burden of Disease study.

Sooji Lee, Hayeon Lee, Yejun Son +1036 more

Ischemic heart disease (IHD) remains a leading cause of death worldwide, with dietary risks being its most significant modifiable factor. Here, using the Global Burden of Diseases, Injuries and Risk Factors Study 2023, we estimated the mortality and disability-adjusted life years from diet-related IHD across 204 countries. In 2023, a suboptimal diet was responsible for 4.06 million (95% uncertainty interval (UI) 0.74-6.22) IHD deaths and 96.84 million (18.82-142.52) IHD disability-adjusted life years. The global age-standardized death rate of IHD attributable to suboptimal diet decreased by 43.92% (95% UI 34.44-53.23) per 100,000 population from 1990 to 2023. Among dietary factors, low intake of nuts and seeds (9.87, 95% UI 2.84-17.12 deaths per 100,000 population), low whole grains (9.22, 4.73-13.67), low fruits (7.25, 1.54-13.34) and high sodium (7.15, 0.92-17.97) were primary contributors to IHD deaths. The burden was particularly pronounced in low- and middle-sociodemographic index countries. By disentangling dietary risk factors, we identified the portion of IHD burden directly modifiable through food interventions.

CIMT combined with BoNT-A regenerates skeletal muscle and improves upper limb function through activating IGF-1/FGFR2 axis in hemiplegic cerebral palsy.

You Wang, Qihong Wu, Xiuying Zhao +16 more

Hemiplegic cerebral palsy (HCP) is a prevalent cause of pediatric motor disability. Constraint-induced movement therapy (CIMT), when combined with botulinum neurotoxin type A (BoNT-A), improves upper limb function and social participation in individuals with HCP. However, the mechanisms underlying the combined interventions remain unclear.

Single-Cell RNA-Sequencing Reveals Cachectic Satellite Cell Population in Muscle of Male Mice With Cancer Cachexia.

Alex Brown, Nicolás Collao, Aisha Saleh +3 more

Cancer cachexia leads to decreases in body mass, lean mass and fat mass, decreased therapeutic potential and ~20% of cancer-related deaths. While several studies have demonstrated changes to components of the muscle microenvironment with cancer cachexia, none have comprehensively assessed changes to cellular dynamics across the duration of cachexia development.

Review of the Pathology of Muscle in Amyotrophic Lateral Sclerosis.

Matthew Katz, Thomas Robertson, Shyuan T Ngo +4 more

In amyotrophic lateral sclerosis (ALS), a central event is the withdrawal of the motor nerve terminal from its target muscle. Whether this defect is driven by faults in the motor neuron or faults that originate within the muscle remains an area of investigation. In this review, we focus on the pathological abnormalities that are found in skeletal muscle, focusing, when possible, on human ALS, with support from ALS animal models. We begin with an overview of skeletal muscle, including a review of muscle fiber type, motor units and the neuromuscular synapse. Next, we provide a description of the clinical and biomarker changes that occur in the muscles of patients with ALS. We provide an extensive account of the histopathological changes that are evident in ALS muscle, such as fiber type grouping, muscle inflammation, protein misfolding, mitochondrial dysfunction, and alterations in neuromuscular junctions and muscle satellite cells. Our review then concludes with an update of metabolic and molecular-genetic changes that are found in ALS muscle. The evidence shows that muscle can be an additional target for therapy in ALS, in combination with therapies targeting neurons and glia within the central nervous system (CNS).

Satellite Glial Cells in Peripheral Nerve Injury and Regeneration.

Linjia Hu, Haimin Lu, Yufan Shen +4 more

Satellite glial cells (SGCs) are morphologically unique peripheral glial cells that surround neuronal somas in sensory, sympathetic, and parasympathetic ganglia. Satellite glial cells communicate with neurons that they ensheathe and form a distinct structural and functional unit. Following peripheral nerve injury, satellite glial cells undergo remarkable morphological changes, including gliosis, and help regulate the microenvironment surrounding neuronal somas. The expression of many satellite glial cell markers such as glial fibrillary acidic protein (GFAP) and connexin-43, pro-inflammatory cytokines, and growth factors in satellite glial cells is altered in these cells. Injury responses of satellite glial cells, particularly the activation of peroxisome proliferator-activated receptor α (PPARα), contribute to enhanced axonal regeneration. Targeting satellite glial cells may therefore offer novel therapeutic strategies for the treatment of peripheral nerve injury.

Co-cultured spheroids of piscine cells as building blocks for cultured fish meat.

Yingfei Su, Shengliang Zhang, Yingqi Jiang +3 more

Cultured meat has emerged as a promising approach to enhancing global food sustainability. Current production methods, however, rely mainly on single-cell-type culture, which fails to replicate the complex composition of conventional meat. In this study, a scaffold-free co-culture system was established to generate structured microtissue comprising highly differentiated muscle and fat cells. Co-cultured spheroids with the ratios of piscine adipose-derived stem cells (PADSCs) to piscine satellite cells (PSCs) being 5:5, 7:3 and 9:1 were investigated, and the result showed that all ratios remained robust and highly viable throughout the differentiation process and successfully induced the formation of bionic tissue containing both myotubes and adipocytes. Based on transcriptome data, the cluster analysis indicated that co-cultured spheroids (the ratio of PADSCs to PSCs was 7:3) were similar to the PADSC spheroids, and the expression levels of cell cycle-related and extracellular matrix-related genes were biased towards those of PADSC spheroids. These results indicated that these co-cultured spheroids held promise as building blocks for further tissue assembly and offered a promising approach for scaling up the production of structured cultured fish meat.

Leuprolide Acetate Promotes Sensory Recovery and Modulates Dorsal Root Ganglion Responses After Sciatic Nerve Transection in Rats.

Irma Hernández-Jasso, Denisse Calderón-Vallejo, José Ávila-Mendoza +5 more

Background/Objectives: Sciatic nerve injuries are among the most common classes of peripheral nerve harm and have a strong impact on quality of life, as well as a significant negative economic impact for patients, society, and governments, since they represent a frequent cause of work-related disabilities and sick leave applications. Following nerve injury, neurons, Schwann, and satellite cells undergo marked changes in phenotype, metabolic activity, neuronal survival, nervous transmission, and an exacerbated activation of the inflammatory response. Leuprolide acetate (LA), a clinically available agonist of gonadotropin-releasing hormone (GnRH), has shown clear neurotrophic properties and is considered a novel potential candidate for treating neural injuries, including sciatic nerve pathologies. This study aimed to analyze the effect of LA treatment on sensory function and dorsal root ganglia (DRG) changes in a rat sciatic nerve full-transection (SNT) model. Methods: Variations in cold and heat sensitivity were assessed using the thermal plate test, while DRG tissue sections were examined for modifications in reactive gliosis by immunofluorescence analysis, and axonal transport using a retrograde tracer. Also, changes in the expression of pro-regenerative genes Stat3, Socs3, Fos, Jun, Atf4, and Limk1 were quantified by qPCR. Results: Our results showed that LA treatment exerted a distinct neurotrophic effect, since it promoted the specific recovery of cold sensitivity, improved axonal transport, regulated the inflammatory response, and modulated the exacerbated expression of pro-regenerative genes in the SNT model. Conclusions: These findings indicate that LA therapy may have the potential to improve sensory recovery in patients with sciatic nerve injuries.

Transcriptome Analysis of miRNAs Involved in the Myogenic Differentiation of Goat Skeletal Muscle Satellite Cells.

Runxiao Luo, Tao Zhong, Linjie Wang +4 more

Skeletal muscle myogenesis is a crucial factor influencing meat production in livestock. MicroRNAs (miRNAs) play a significant role in skeletal muscle myogenesis. The objective of this study was to identify key miRNAs involved in the process of goat skeletal muscle satellite cell (MuSC) differentiation into myotubes. We performed miRNA expression profiling analysis during the proliferation phase (cultured in growth medium, GM) and the differentiation phase (cultured in differentiation medium for 1 day and 5 days, classified as DM1 and DM5, respectively) of goat skeletal muscle satellite cells (MuSCs). A total of 1846 miRNAs were identified in MuSC samples, of which 677 differentially expressed miRNAs (DEmiRNAs) were screened through pairwise comparisons across three groups (GM vs. DM1, GM vs. DM5, and DM1 vs. DM5), and the results were further confirmed by a quantitative real-time PCR assay. Time-series expression profiling facilitated the categorization of the DEmiRNAs into eight distinct clusters, one of which demonstrated a significantly downregulated expression pattern (p < 0.05). Functional enrichment analysis revealed that the target genes of DEmiRNAs are involved in several pathways that are critical for myogenesis, including Hippo, TGF-β, MAPK and cell adhesion molecules. Interaction network analysis identified 19 miRNAs and 56 mRNAs associated with muscle cell development. Notably, novel-m0047-5p emerged as a key regulator, exhibiting strong negative correlations (r = -0.88 to -0.89, q < 0.01) with muscle-related target genes FOSB, CPT1B, and MYOZ2. These findings elucidate miRNA-mediated regulatory networks in goat myogenesis and provide candidate molecular targets for genetic improvement of meat production traits.

Inflammaging-induced TRAF3 degradation impairs AMP biosynthesis to drive sarcopenia.

Jinbo Li, Yaning Xing, Jinxiao Fan +10 more

Inflammaging is a recognized driver of age-related pathologies, yet its specific mechanistic link to sarcopenia remains poorly understood. Here, we identified a significant reduction of TNF receptor-associated factor 3 (TRAF3) in myoblasts exposed to aged serum and in skeletal muscles from both aging mice and humans. Genetic deletion of TRAF3 in myocytes or satellite cells induced early-onset sarcopenia and impaired regeneration, independent of non-canonical NF-κB signaling. Mechanistically, TRAF3 maintains energy homeostasis by stabilizing the key metabolic enzyme, adenylosuccinate lyase (ADSL), and its loss impairs AMP biosynthesis and ATP production. Muscle-specific TRAF3 restoration or AMP supplementation rescued sarcopenic phenotypes in TRAF3-deficient mice. Notably, neutrophil-derived transforming growth factor β1 (TGFβ1) caused IAP-mediated ubiquitination and degradation of TRAF3 in aged mice--a process reversible by the IAP inhibitor SM-164. Inducible neutrophil-specific TGFβ1 deletion prevented age-related sarcopenia. Our study establishes that TRAF3 is a key protective factor in muscle aging, and its loss mechanistically links inflammaging to bioenergetic deficits, suggesting new strategies to prevent age-related muscle wasting.

Cellular Senescence in Skeletal Muscle: Myogenic and Non-Myogenic Cell Populations, Mechanisms, and Therapeutic Opportunities.

Konstantinos Papanikolaou, Angad Yadav, Robert T Mankowski +5 more

Skeletal muscle plays a central role in systemic metabolism, physical function, and overall health. Aging and disease diminish the ability of myogenic and non-myogenic skeletal muscle cells to coordinate adaptation and repair, but the mechanisms underlying this decline are not fully understood. Growing evidence implicates cellular senescence, a stress response marked by irreversible cell-cycle arrest and pro-inflammatory signaling, as a key contributor to muscle pathology. In this review, we synthesize current insights into the molecular mechanisms that govern cellular senescence in skeletal muscle, its effects on myogenic and non-myogenic cell populations, and recent technologies that have clarified key aspects of senescence biology. We further explore emerging therapeutic strategies aimed at targeting senescent cells and discuss key knowledge gaps that must be addressed to advance our understanding of senescent myogenic and non-myogenic cells in skeletal muscle.

The expression characteristics of miR-206-3p in musculoskeletal tissue and its clinical significance.

Khan Akhtar Ali, Xuefeng Yuan, Tianxiang Cui +3 more

Osteosarcopenia, a comorbidity of osteoporosis and sarcopenia in the elderly, involves bone-muscle crosstalk, but its core molecular mechanism remains unclear. miR-206 is traditionally considered muscle-specific; this study explores miR-206-3p's expression in musculoskeletal tissue and correlation with clinical parameters.

Involvement of peripheral and central sensitization in prolonged mechanical allodynia of the tongue in a rat.

Saki Kishimoto, Sho Katsura, Yoshie Okamoto +3 more

This study aimed to characterize peripheral and central sensitization in mechanical allodynia of the tongue induced by sleep-related disorders, neuropathic pain, and inflammatory pain. Male rats were exposed to chronic intermittent hypoxia (CIH) for 16 days using an obstructive sleep apnea model. Lingual nerve injury (LNI) was induced to establish a neuropathic tongue pain model, while complete Freund's adjuvant was injected into the tongue to establish a tongue inflammation (TI) model. The expression levels of calcitonin gene-related peptide (CGRP), hypoxia-inducible factor (HIF)-1α, piezo-type mechanosensitive ion channel component 2 (Piezo2), transient receptor potential cation channel subfamily V member 4 (TRPV4), and glial fibrillary acidic protein (GFAP) in the trigeminal ganglion (TG) and cFos in the trigeminal spinal subnucleus were determined using immunohistochemistry on day 16. All CIH, LNI, and TI rat models exhibited prolonged mechanical allodynia of the tongue. CIH and TI increased the number of CGRP-immunoreactive (IR) neurons and HIF-1α-IR cells. However, only CIH increased the number of Piezo2-IR neurons and GFAP-positive satellite glial cells. The number of TRPV4-IR neurons was elevated in the LNI and TI groups but not in the CIH group. Only CIH induced persistent cFos expression in the trigeminal spinal subnucleus caudalis, indicating long-lasting central sensitization. These findings indicate that CIH-induced tongue pain arises through distinct peripheral and central sensitization processes, highlighting the diverse mechanisms underlying chronic mechanical allodynia of the tongue.

Metabolic and cellular physiological differences between embryonic breast and leg muscle satellite cells in chickens.

Jongryun Kim, Jeongeun Lee, Dongjin Yu +6 more

This study aimed to compare the anatomical characteristics of embryonic chicken muscle satellite cells (CMSCs) derived from breast and leg muscles of 18-day-old embryos. We analyzed the cellular behaviors related to proliferation, metabolism, and differentiation capacity. Breast-derived CMSCs exhibited significantly higher proliferation rates and accelerated cell cycle progression, as evidenced by a higher S phase distribution and lower G2/M phase distribution compared to leg-derived CMSCs. In addition, immunofluorescence staining for myogenic regulatory factors revealed that breast-derived CMSCs exhibited higher expression levels of paired box protein 7 (PAX7), consistent with elevated PAX7 and myogenic differentiation 1 (MYOD) mRNA expression compared with leg-derived CMSCs. In contrast, leg-derived CMSCs showed significantly higher expression of myogenin (MYOG). Moreover, leg-derived CMSCs exhibited significantly higher mitochondrial respiratory activity indices, including oxygen consumption rate and basal respiration. In differentiation capacity analysis, the leg-derived CMSCs formed structurally more developed myotubes, and the expression of muscle-specific genes (MYOD, MYOG, MYH1E, MYH7, TNNI1, TNNI2) was also significantly higher. These findings suggest that breast-derived CMSCs exhibit superior proliferative capacity, while leg-derived CMSCs possess enhanced myogenic differentiation potential, as supported by their increased oxidative phosphorylation activity and elevated expression of differentiation-related markers. In conclusion, the anatomical origin of CMSCs significantly influences their proliferative and differentiation capacities as well as their metabolic properties, providing a valuable basis for selecting optimal cell sources for cultured meat production and meat quality improvement.

Transcriptional competence defines the heterochromatin nucleating potential of isolated MSR units.

Yi-Hsuan Lo, Nicholas Shukeir, Galina Erikson +6 more

In mouse cells, constitutive heterochromatin is associated with underlying arrays of A/T-rich DNA repeat elements, called the major satellite repeats (MaSat or MSR). We examine >18,000 MSR copies in mouse ES cells and identify that heterochromatin forms only at transcriptionally competent MSR units. To directly dissect the function of MSR DNA, we insert isolated MSR units into an inert genomic region that is repeat- and gene-free. Insertion of three or more intact MSR units induces heterochromatic histone marks, recruitment of HP1 and incorporation of histone H1. Only transcriptionally competent MSR units, but not permutated MSR variants or LINE1 5'UTR elements, nucleate de novo heterochromatin. MSR-derived transcription is bi-directional and MSR-originating transcripts are attenuated by the RNAPII-associated Integrator complex. Instructively, multi-copy intact MSR units impart an unwound DNA template that facilitates RNAPII engagement. Together, this study uncovers a DNA/RNA-based logic and transcription-coupled mechanism for the nucleation of heterochromatin.

Interaction of Sepsis, Disuse, and Aging on Skeletal Muscle Function and Remodeling in Male and Female Mice.

Diana C Muller, Franccesco P Boeno, Gisienne Reis +7 more

Sepsis is associated with skeletal muscle weakness and atrophy, particularly in older and immobilized patients; however, how sepsis interacts with disuse, reloading, aging, and biological sex remains poorly defined.

Enhancing cultured meat production with ginseng leaf-stem extract: a novel supplementation approach to promote porcine muscle stem cell growth.

Su Min Park, Do Hyun Kim, Hyuk Cheol Kwon +4 more

Ginsenosides, including ginsenoside Re (G-Re), exert muscle-protective effects, and ginseng leaves and stems are rich in G-Re. Cultured meat has garnered attention as a sustainable alternative to conventional meat production methods. The proliferation and differentiation of muscle satellite cells (MuSCs) are essential for meat production. Herein, we examined the effects of ginseng leaf-stem extract (G-LSE) on the growth, differentiation, and myotube formation of MuSCs. The G-Re content of G-LSE was quantified using LC-MS/MS. MuSCs were treated with G-LSE (0, 0.25, 0.5, 1, 2, and 4 mg/mL for 48 h). Cell proliferation and cell cycle analyses were performed. Myogenic factors, the AKT/mammalian target of rapamycin (mTOR) signaling pathway, and FoxO3a were detected using real-time PCR, Western blotting, and immunofluorescence analyses. At concentrations of 0.25, 0.5, and 1 mg/mL, G-LSE enhanced cell proliferation over 7 days in a concentration-dependent manner. G-LSE also promoted cell cycle progression. Treatment with G-LSE increased mRNA levels of myogenic differentiation 1 (MyoD), myogenin (MyoG), and myosin heavy chain after 7 days in a concentration-dependent manner. G-LSE also elevated cellular protein levels of MyoD and MyoG. A 7-day treatment with 1 mg/mL G-LSE maintained high MyoG levels and morphological transition to myotubes. Myogenic proliferation and differentiation were mediated via AKT/mTOR activation and inhibition of FoxO3a nuclear translocation. G-LSE promotes porcine MuSC proliferation and differentiation by activating AKT/mTOR signaling and inhibiting FoxO3a nuclear translocation. G-LSE could be a novel plant-derived supplement for promoting MuSC growth and differentiation, particularly in cultured meat production.