Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy DOI Open Access
Maggie Lutz,

Miranda Levanti,

Rebekah Karns

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(13), P. 10650 - 10650

Published: June 26, 2023

Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease associated with toxic RNA containing expanded CUG repeats. The developing therapeutic approaches to DM1 target mutant or correct early events downstream of the RNA. We have previously described benefits correction GSK3β-CUGBP1 pathway in mice (HSALR model) expressing 250 repeats using GSK3 inhibitor tideglusib (TG). Here, we show that TG treatments corrected expression ~17% genes misregulated mice, including involved cell transport, development and differentiation. chloride channel (Clcn1), key trigger myotonia DM1, was also by TG. found long (DMSXL beneficial not only at prenatal postnatal stages, but during adulthood. Using mouse model dysregulated CUGBP1, which mimics alterations showed CUGBP1 contributes toxicity changing gene causing CNS abnormalities. These data critical role muscle pathologies, suggesting inhibitors patients different forms DM1.

Language: Английский

Neuromuscular Dysfunction Precedes Cognitive Impairment in a Mouse Model of Alzheimer’s Disease DOI Creative Commons
Matthew H. Brisendine, Anna S. Nichenko, Aloka B. Bandara

et al.

Function, Journal Year: 2023, Volume and Issue: 5(1)

Published: Nov. 23, 2023

Abstract Alzheimer’s disease (AD) develops along a continuum that spans years prior to diagnosis. Decreased muscle function and mitochondrial respiration occur earlier in those develop AD; however, it is unknown what causes these peripheral phenotypes of the brain. Exercise promotes muscle, mitochondria, cognitive health proposed be potential therapeutic for AD, but no study has investigated how skeletal adapts exercise training an AD-like context. Utilizing 5xFAD mice, AD model ad-like pathology impairments around 6 mo age, we examined vivo neuromuscular adapations (mitochondrial RNA sequencing) before manifestation overt impairment. We found mice dysfunction beginning as early 4 characterized by impaired nerve-stimulated torque production compound nerve action sciatic nerve. Furthermore, had altered, sex-dependent, adaptive responses gene expression) absence Changes systems, specifically neural communication may harbingers have implications lifestyle interventions, like exercise, AD.

Language: Английский

Citations

9
Belt electrode tetanus muscle stimulation reduces denervation-induced atrophy of rat multiple skeletal muscle groups DOI Creative Commons
Hiroyuki Uno,

Shohei Kamiya,

Ryuji Akimoto

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: March 11, 2024

Abstract Belt electrode-skeletal muscle electrical stimulation (B-SES) involves the use of belt-shaped electrodes to contract multiple groups simultaneously. Twitch contractions have been demonstrated protect against denervation-induced atrophy in rats, possibly through mitochondrial biosynthesis. This study examined whether inducing tetanus with B-SES suppresses and identified underlying molecular mechanisms. We evaluated effects acute (60 Hz, 5 min) chronic min, every alternate day for one week) on tibialis anterior (TA) gastrocnemius (GAS) muscles Sprague–Dawley rats using belt attached both ankle joints. After stimulation, a significant decrease glycogen content was observed left right TA GAS, suggesting that causes simultaneous groups. enhanced p70S6K phosphorylation, an indicator mechanistic target rapamycin complex 1 activity. During stimulations, were divided into control (CONT), (DEN), DEN + electrically stimulated (DEN ES) seven days treatment, wet weight (n = 8–11 each group) fiber cross-sectional area (CSA, n 6 GAS reduced ES compared CON group. The group showed significantly higher CSA than those Although RNA-seq pathway analysis suggested biogenesis is critical event this phenomenon, no difference. In contrast, ribosomal RNA 28S 18S 6) levels group, even though ribosome by stimulation. mRNA proteolytic molecules atrogin-1 MuRF1 CONT. However, they more suppressed DEN. conclusion, tetanic ankles effectively Furthermore, biosynthesis plays vital role phenomenon.

Language: Английский

Citations

3
Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis DOI Creative Commons
Peter J. Richardson, Daniel P. Smith,

Alex de Giorgio

et al.

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: Oct. 12, 2023

Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As other diseases, it likely that drugs will need to target processes be effective. We review here the role of Janus kinase (JAK)/Signal transducer activator transcription (STAT) signalling in ALS, confirm association this fundamental ALS using BenevolentAI Knowledge Graph, demonstrate inhibitors pathway could reduce pathophysiology neurons, glia, muscle fibres, blood cells. Specifically, we suggest inhibition JAK enzymes by approved known as Jakinibs STAT3 activation modify progress disease. Analysis highlights baricitinib suitable candidate due its ability penetrate central nervous system exert beneficial effects on immune system. Therefore, recommend drug tested appropriately designed clinical trials for ALS.

Language: Английский

Citations

7
Screen for autophagy-related biomarkers in osteoarthritis based on bioinformatic analysis DOI Open Access
Chao Liu

Biocell, Journal Year: 2024, Volume and Issue: 48(2), P. 339 - 351

Published: Jan. 1, 2024

Introduction: Osteoarthritis (OA) is still an important health problem, and understanding its pathological mechanisms essential for diagnosis treatment.There evidence that autophagy may play a role in OA progression, but the exact mechanism remains unclear.Methods: In this study, we adopted multi-prong approach to systematically identify key autophagy-related genes (ARGs) associated with OA.Through weighted gene coexpression network analysis, initially identified significant modules OA.Subsequent differential analysis performed on normal specimens.Further later using MCC algorithm highlighted hub ARGs.These were then incorporated into prediction model of OA.In addition, expression patterns these DEGs verified by vitro experiments.Results: A total 104 differentially expressed (DEGs) which 102 up-regulated 2 down-regulated.These closely related signaling pathways, such as PI3K-Akt pathway, IL-17 pathway osteoclast differentiation.Further 10 ARGs, among ATF3, CYCS, FOXO3, KLF6, NFKBIA SOCS3 particularly significant, included OA, showed robust ability area under curve 0.783.In experiments confirmed pattern was consistent our prediction.Conclusion: summary, comprehensive not only provides new insights molecular basis also suggests potential biomarkers diagnosis.

Language: Английский

Citations

2
Muscle fibrosis, NF-κB, and TGF-β are differentially altered in two models of paralysis (Botox vs. Neurectomy) DOI

James T. Redden,

Jingyao Deng, David J. Cohen

et al.

Advances in Wound Care, Journal Year: 2024, Volume and Issue: unknown

Published: June 15, 2024

: Volumetric muscle loss results in intramuscular axotomy, denervating distal to the injury and leading paralysis, denervation, of function. Once nerve is damaged, paralyzed skeletal will atrophy accumulate noncontractile connective tissue. The objective this study was determine differences tissue, atrophy, inflammatory signaling between two paralysis models, botulinum toxin (Botox), which blocks acetylcholine transmission while keeping nerves intact, neurectomy, eliminates all nerve-to-muscle signaling.

Language: Английский

Citations

2
l‐Carnitine relieves cachexia‐related skeletal muscle fibrosis by inducing deltex E3 ubiquitin ligase 3L to negatively regulate the Runx2/COL1A1 axis DOI Creative Commons

Zong-liang Lu,

Li Wang, Zhenyu Huo

et al.

Journal of Cachexia Sarcopenia and Muscle, Journal Year: 2024, Volume and Issue: 15(5), P. 1953 - 1964

Published: Aug. 2, 2024

Abstract Background Cancer cachexia‐induced skeletal muscle fibrosis (SMF) impairs regeneration, alters the structure and function, reduces efficacy of anticancer drugs, diminishes patient's quality life shortens overall survival. RUNX family transcription factor 2 (Runx2), a factor, collagen type I alpha 1 chain (COL1A1), principal constituent SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. l ‐Carnitine, marker cancer cachexia, can alleviate in liver kidney models; however, its role cachexia‐associated involvement process remain unexplored. Methods Female C57 mice (48 weeks old) were inoculated subcutaneously MC38 cells establish cachexia model. A 5 mg/kg dose ‐carnitine or an equivalent volume water was administered for 14 days via oral gavage, followed by assessments function (grip strength) fibrosis. To elucidate interplay between deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis transforming growth beta 1‐stimulated NIH/3T3 cells, suite molecular techniques, including quantitative real‐time PCR, western blot analysis, co‐immunoprecipitation, docking, immunofluorescence Duolink assays, used. The relevance DTX3L/Runx2/COL1A1 gastrocnemius also explored vivo Results ‐Carnitine supplementation reduced declines grip strength (>88.2%, P < 0.05) fibre area within (>57.9%, 0.05). At dose, suppressed alpha‐smooth actin (α‐SMA) protein expression, which are markers SMF myofibroblasts. Analyses TRRUST database indicated that regulates both COL1A2. In vitro, diminished levels promoted ubiquitination. Overexpression abolished effects on α‐SMA. Co‐immunoprecipitation, assays confirmed interaction DTX3L Runx2, enhancing this promote restored those observed under non‐cachectic conditions, vitro vivo. Knockdown α‐SMA vitro. expression negatively correlated untreated cells. Conclusions This study revealed previously unrecognized link demonstrated exerted significant therapeutic impact potentially through upregulation DTX3L.

Language: Английский

Citations

2
Transcriptomic, Proteomic, and Morphologic Characterization of Healing in Volumetric Muscle Loss DOI
Raphael J. Crum, Scott A. Johnson, Peng Jiang

et al.

Tissue Engineering Part A, Journal Year: 2022, Volume and Issue: 28(23-24), P. 941 - 957

Published: Aug. 30, 2022

Skeletal muscle has a robust, inherent ability to regenerate in response injury from acute chronic. In severe trauma, however, complete regeneration is not possible, resulting permanent loss of skeletal tissue referred as volumetric (VML). There are few consistently reliable therapeutic or surgical options address VML. A major limitation investigation possible therapies the absence well-characterized large animal model. this study, we present results comprehensive transcriptomic, proteomic, and morphologic characterization wound healing following VML novel canine model which compare nine-patient cohort combat-associated The translationally relevant it provides both regional (spatial) temporal map processes that occur human Collectively, these data show spatiotemporal properties framework system applicable future studies investigating for Impact Statement (VML) translational

Language: Английский

Citations

7
The role of ZEB1 in mediating the protective effects of metformin on skeletal muscle atrophy DOI Creative Commons

Peiyu Jia,

Ji Che,

Xiaoting Xie

et al.

Journal of Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 156(2), P. 57 - 68

Published: July 17, 2024

Metformin is an important antidiabetic drug that has the potential to reduce skeletal muscle atrophy and promote differentiation of cells. However, exact molecular mechanism underlying these functions remains unclear. Previous studies revealed transcription factor zinc finger E-box-binding homeobox 1 (ZEB1), which participates in tumor progression, inhibits atrophy. Therefore, we hypothesized protective effect metformin might be related ZEB1. We investigated positive on IL-1β-induced by regulating ZEB1 vitro vivo. Compared with normal cell group, metformin-treated group presented increased myotube diameters reduced expression levels atrophy-marker proteins. Moreover, was hindered, when artificially interfered mouse myoblast (C2C12) cells via ZEB1-specific small interfering RNA (si-ZEB1). In response inflammatory stimulation, treatment three proteins, MHC, MyoD, myogenin, whereas si-ZEB1 partially counteracted effects. marked induced a model administration lipopolysaccharide (LPS) muscles lower limbs. Over 4-week period intragastric administration, ameliorated alleviated stimulated differentiation. Overall, our findings may provide better understanding effects suggest as therapeutic drug.

Language: Английский

Citations

1
Treatment of Denervated Muscle Atrophy by Injectable Dual-responsive Hydrogels Loaded with Extracellular Vesicles DOI Creative Commons
Jianzhong Du, Ziheng Bu, Jianxing Jing

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

Abstract Denervated muscle atrophy is a common complication following nerve injury, which often leads to irreversible fibrosis due low treatment efficiency. Recently, bioactive substances such as extracellular vesicles (EVs) have been emerging an effective therapeutic modality for atrophy. However, the complicated microenvironments of denervated could reduce delivery efficiency and even result in deactivation EVs. To meet this challenge, ultrasound pH-responsive anti-inflammatory injectable hydrogel was developed, can effectively load deliver stem cells derived EVs with satisfactory outcomes Carboxymethyl chitosan, oxidized chondrotin sulfate cystamine dihydrochloride were crosslinked situ by Schiff base reaction form hydrogel, where reversible covalent bond would break under acidic environments promote degradation cargo release. Meanwhile, loaded isolated from human umbilial cord mesenchymal cells(HUC-MSCs) release controlled manner upon facile pH/ultrasound manipulation. The experimental results confirmed that (EVs@UR-gel) preserving function. After six weeks reconstruction, maximum strength closely related function, circumference, wet weight, be restored 89.53 ± 0.96%, 76.02 7.49%, 88.0 2.65% healthy state, sciatic index (SFI) -0.11 0.09, respectively. Overall, provided new platform maintain long-term vivo bioactivity EVs, achieve tunable at site based on state disease, restore morphology function promising approach treating

Language: Английский

Citations

1
Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy DOI Open Access
Maggie Lutz,

Miranda Levanti,

Rebekah Karns

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(13), P. 10650 - 10650

Published: June 26, 2023

Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease associated with toxic RNA containing expanded CUG repeats. The developing therapeutic approaches to DM1 target mutant or correct early events downstream of the RNA. We have previously described benefits correction GSK3β-CUGBP1 pathway in mice (HSALR model) expressing 250 repeats using GSK3 inhibitor tideglusib (TG). Here, we show that TG treatments corrected expression ~17% genes misregulated mice, including involved cell transport, development and differentiation. chloride channel (Clcn1), key trigger myotonia DM1, was also by TG. found long (DMSXL beneficial not only at prenatal postnatal stages, but during adulthood. Using mouse model dysregulated CUGBP1, which mimics alterations showed CUGBP1 contributes toxicity changing gene causing CNS abnormalities. These data critical role muscle pathologies, suggesting inhibitors patients different forms DM1.

Language: Английский

Citations

3