Myospreader improves gene editing in skeletal muscle by myonuclear propagation DOI Creative Commons
Kiril Poukalov, M. Carmen Valero,

Derek R. Muscato

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 6, 2023

Successful CRISPR/Cas9-based gene editing in skeletal muscle is dependent on efficient propagation of Cas9 to all myonuclei the myofiber. However, nuclear-targeted therapy cargos are strongly restricted their myonuclear domain origin. By screening nuclear localization signals and export signals, we identify “Myospreader”, a combination short peptide sequences that promotes propagation. Appending Myospreader enhances protein stability myoblasts myofibers. AAV-delivered dCas9 better inhibits transcription toxic RNA myotonic dystrophy mouse model. Furthermore, achieves higher rates CRISPR reporter Duchenne muscular models. reveals design principles relevant therapies highlights importance spatial dimension therapeutic development.

Language: Английский

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases DOI Creative Commons
Qian Lu, Yanli Zhu, Chao Deng

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 1, 2024

Abstract Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC), was discovered more than a quarter-century ago. PGC-1s are essential coordinators many vital cellular events, including mitochondrial functions, oxidative stress, endoplasmic reticulum homeostasis, inflammation. Accumulating evidence has shown that implicated in diseases, such as cancers, cardiac diseases cardiovascular neurological disorders, kidney motor system metabolic disorders. Examining the upstream modulators co-activated partners identifying critical biological events modulated by downstream effectors contribute to presentation elaborate network PGC-1s. Furthermore, discussing correlation between well summarizing therapy targeting helps make individualized precise intervention methods. In this review, we summarize basic knowledge regarding molecular regulatory network, discuss physio-pathological roles human review application PGC-1s, diagnostic prognostic value several therapies pre-clinical studies, suggest directions for future investigations. This presents immense potential treatment hopefully facilitates promotion new therapeutic targets.

Language: Английский

Citations

79
Meteorin‐like protein/METRNL/Interleukin‐41 ameliorates atopic dermatitis‐like inflammation DOI Creative Commons

Danqi Huang,

Xiuting Liu,

Xun Gao

et al.

Allergy, Journal Year: 2024, Volume and Issue: 80(2), P. 474 - 488

Published: May 10, 2024

Meteorin-like protein (METRNL)/Interleukin-41 (IL-41) is a novel immune-secreted cytokine/myokine involved in several inflammatory diseases. However, how METRNL exerts its regulatory properties on skin inflammation remains elusive. This study aims to elucidate the functionality and mechanism of atopic dermatitis (AD). levels were determined serum samples from patients with AD subsequently verified vitamin D3 analogue MC903-induced AD-like mice model. The cellular target activity was identified by multiplex immunostaining, single-cell RNA-seq RNA-seq. significantly upregulated lesions compared healthy controls (p <.05). Following repeated MC903 exposure, model displayed elevated both ears serum. Administration recombinant murine (rmMETRNL) ameliorated allergic hallmarks mice, whereas blocking signaling led opposite. enhanced β-Catenin activation, limited expression Th2-related molecules that attract accumulation Arginase-1 (Arg1)hi macrophages, dendritic cells, activated mast cells. can bind KIT receptor alleviate inhibiting expansion immune downregulating gene regulating level active WNT pathway molecule β-Catenin.

Language: Английский

Citations

9
AAV‐Mediated nuclear localized PGC1α4 delivery in muscle ameliorates sarcopenia and aging‐associated metabolic dysfunctions DOI Creative Commons
Mingwei Guo, Jun Zhang, Ying Ma

et al.

Aging Cell, Journal Year: 2023, Volume and Issue: 22(10)

Published: Aug. 16, 2023

Sarcopenia is characterized of muscle mass loss and functional decline in elder individuals which severely affects human physical activity, metabolic homeostasis, life quality. Physical exercise considered effective combating atrophy sarcopenia, yet it not feasible to elders with limited mobility. PGC-1α4, a short isoform PGC-1α, strongly induced under resistance training, promotes hypertrophy. In the present study, we showed that transcriptional levels nuclear localization PGC1α4 was reduced during aging, accompanied dystrophic morphology, gene programs. We thus designed NLS-PGC1α4 ectopically express myotubes enhance maintain its location nucleus. Indeed, overexpression increased sizes myotubes. addition, by utilizing AAV-NLS-PGC1α4 delivery into gastrocnemius muscle, found could improve sarcopenia grip strength, weights, fiber size molecular phenotypes, alleviate age-associated adiposity, insulin hepatic steatosis, altered signatures. Mechanistically, demonstrated NLS-PGC-1α4 improved signaling enhanced glucose uptake skeletal muscle. Besides, via RNA-seq analysis, identified myokines IGF1 METRNL as potential targets possibly mediate improvement adipose tissue functionality systemic energy metabolism aged mice. Moreover, negative correlation between age Together, our results revealed improves physiology systematic homeostasis aging suggested potent therapeutic strategy against aging-associated diseases.

Language: Английский

Citations

15
Intermittent glucocorticoid treatment improves muscle metabolism via the PGC1α/Lipin1 axis in an aging-related sarcopenia model DOI Creative Commons

Ashok D. Prabakaran,

K. S. McFarland, Karen Miz

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(11)

Published: May 3, 2024

Sarcopenia burdens the elderly population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are missing. The glucocorticoid prednisone remodels metabolism based on frequency intake, but its mechanisms in sarcopenia unknown. We found that once-weekly intermittent rescued quality aged 24-month-old mice levels comparable young 4-month-old mice. discovered an age- sex-independent receptor transactivation program encompassing PGC1α co-factor Lipin1. Treatment coordinately improved mitochondrial abundance isoform 1 mass 4 myocyte-specific PGC1α, which was required for treatment-driven increase carbon shuttling from glucose amino acid biogenesis. also probed Lipin1 as non-redundant factor coaxing upregulation stimulation oxidative anabolic effects. Our study unveils aging-resistant druggable myocytes sarcopenia.

Language: Английский

Citations

5
Adeno-Associated Virus Vectors: Principles, Practices, and Prospects in Gene Therapy DOI Creative Commons
Limor Zwi‐Dantsis,

Saira Mohamed,

Giulia Massaro

et al.

Viruses, Journal Year: 2025, Volume and Issue: 17(2), P. 239 - 239

Published: Feb. 9, 2025

Gene therapy offers promising potential as an efficacious and long-lasting therapeutic option for genetic conditions, by correcting defective mutations using engineered vectors to deliver material host cells. Among these vectors, adeno-associated viruses (AAVs) stand out their efficiency, versatility, safety, making them one of the leading platforms in gene therapy. The enormous AAVs has been demonstrated through use over 225 clinical trials FDA’s approval six AAV-based products, positioning at forefront field. This review highlights evolution current applications therapy, focusing on successes, ongoing developments, manufacturing processes required rapid commercial growth anticipated AAV market. It also discusses broader implications advancements future strategies targeting more complex multi-systemic conditions biological such aging. Finally, we explore some major challenges currently confronting

Language: Английский

Citations

0
Skeletal muscle growth to combat diabetes and obesity: the potential role of muscle‐secreted factors DOI Creative Commons
Mitchell J. Sammut,

Benjamin R. Thorne,

C.W. James Melling

et al.

Obesity, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Abstract As the prevalence of obesity and metabolic disease continues to climb, need for effective therapeutic interventions remains high. The growth skeletal muscle (SkM) greatly influences systemic metabolism across whole body, making this tissue an important target combat rise dysfunction. Transgenic rodent models targeted SkM exhibit profound improvements in various remote tissues, including adipose liver. It is currently unclear how selective stimulation alters distant tissues; however, evidence suggests that muscle‐secreted factors may be involved. Here, we aim provide basic biomedical researchers with a summary current knowledge regarding regulated by anabolic pathways proteins SkM, as well their effects, implicate them whole‐body effects growth. In review, also identify several gaps field, future directions investigation, implications such resistance exercise pharmacology. image

Language: Английский

Citations

0
Polyplex Nanomicelle‐Mediated Pgc‐1α4 mRNA Delivery Via Hydrodynamic Limb Vein Injection Enhances Damage Resistance in Duchenne Muscular Dystrophy Mice DOI Creative Commons
Xuan Du, Hideyuki Nakanishi, Takashi Yamada

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, leading to absence of dystrophin and progressive muscle degeneration. Current therapeutic strategies, such as exon-skipping gene therapy, face limitations including truncated production safety concerns. To address these issues, a novel mRNA-based therapy explored using polyplex nanomicelles deliver mRNA encoding peroxisome proliferator-activated receptor gamma coactivator 1 alpha isoform 4 (PGC-1α4) via hydrodynamic limb vein (HLV) administration. Using an vivo torque measurement technique, it observed that nanomicelle-delivered Pgc-1α4 significantly improved damage resistance mitochondrial activity mdx mice. Specifically, HLV administration dystrophic muscles relieved reduction myofiber injury induced eccentric contraction (ECC), boosted metabolic expression, enhanced oxidative capacity. In comparison, lipid nanoparticles (LNPs), widely used delivery system, does not achieve similar protective effects, likely due their intrinsic immunogenicity. This foundational proof-of-concept study highlights potential therapeutics for treatment neuromuscular diseases demonstrates capability safe efficient system applications.

Language: Английский

Citations

0
AAV capsids target muscle resident cells with different efficiencies - a comparative study between AAV8, AAVMYO and AAVMYO2 DOI Creative Commons

Timothy J McGowan,

Nicolas Lewerenz,

Eleonora Maino

et al.

Molecular Therapy — Methods & Clinical Development, Journal Year: 2025, Volume and Issue: 33(2), P. 101451 - 101451

Published: March 14, 2025

Language: Английский

Citations

0
Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration DOI Creative Commons

Donghui Na,

Z. Zhang,

Meng Meng

et al.

Cellular and Molecular Neurobiology, Journal Year: 2025, Volume and Issue: 45(1)

Published: April 21, 2025

Abstract Aging is characterized by a gradual decline in physiological functions, with brain aging being major risk factor for numerous neurodegenerative diseases. Given the brain’s high energy demands, maintaining an adequate ATP supply crucial its proper function. However, advancing age, mitochondria dysfunction and deteriorating metabolism lead to reduced overall production impaired mitochondrial quality control (MQC). As result, promoting healthy has become key focus contemporary research. This review examines relationship between aging, highlighting connection MQC metabolism, proposes strategies delay targeting metabolism.

Language: Английский

Citations

0
Myospreader improves gene editing in skeletal muscle by myonuclear propagation DOI Creative Commons
Kiril Poukalov, M. Carmen Valero,

Derek R. Muscato

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(19)

Published: April 30, 2024

Successful CRISPR/Cas9-based gene editing in skeletal muscle is dependent on efficient propagation of Cas9 to all myonuclei the myofiber. However, nuclear-targeted therapy cargos are strongly restricted their myonuclear domain origin. By screening nuclear localization signals and export signals, we identify “Myospreader,” a combination short peptide sequences that promotes propagation. Appending Myospreader enhances protein stability myoblasts myofibers. AAV-delivered dCas9 better inhibits transcription toxic RNA myotonic dystrophy mouse model. Furthermore, achieves higher rates CRISPR reporter Duchenne muscular models. reveals design principles relevant therapies highlights importance spatial dimension therapeutic development.

Language: Английский

Citations

3