Changes of Gene Expression Patterns of Muscle Pathophysiology-Related Transcription Factors During Denervated Muscle Atrophy

Yang, Xiaoming; Li, Ming; Ji, Yanan; Lin, Yinghao; Xu, Lai; Gu, Xiaosong; Sun, Hualin; Wang, Wei; Shen, Yuntian; Liu, Hua; Zhu, Jianwei

doi:10.3389/fphys.2022.923190

Cited by 12 publications

(6 citation statements)

References 93 publications

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“…Myogenin expression is upregulated in denervated muscle and participates in the expression of atrophic genes 50 . Tead4 and Klf5 are also upregulated in atrophic muscle 52 , 53 . In cooperation with Myogenin, Tead4 and Klf5 could synergistically activate the expression of an atrophic gene regulatory program in diseased myofibers.…”

Section: Discussionmentioning

confidence: 99%

Opposing gene regulatory programs governing myofiber development and maturation revealed at single nucleus resolution

et al. 2023

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Skeletal muscle fibers express distinct gene programs during development and maturation, but the underlying gene regulatory networks that confer stage-specific myofiber properties remain unknown. To decipher these distinctive gene programs and how they respond to neural activity, we generated a combined multi-omic single-nucleus RNA-seq and ATAC-seq atlas of mouse skeletal muscle development at multiple stages of embryonic, fetal, and postnatal life. We found that Myogenin, Klf5, and Tead4 form a transcriptional complex that synergistically activates the expression of muscle genes in developing myofibers. During myofiber maturation, the transcription factor Maf acts as a transcriptional switch to activate the mature fast muscle gene program. In skeletal muscles of mutant mice lacking voltage-gated L-type Ca2+ channels (Cav1.1), Maf expression and myofiber maturation are impaired. These findings provide a transcriptional atlas of muscle development and reveal genetic links between myofiber formation, maturation, and contraction.

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Section: Discussionmentioning

confidence: 99%

Opposing gene regulatory programs governing myofiber development and maturation revealed at single nucleus resolution

et al. 2023

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“…Besides Runx1 , TG normalized several critical transcription factors misregulated in HSA LR muscle, including Tead4 and Myf6 , which are also up-regulated in denervated muscle atrophy [ 30 ]. TEAD4 belongs to a family of transcription factors that bind a muscle-specific cytidine–adenosine–thymidine element (MCAT) in the gene regulatory regions, promoting myogenesis [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy

Lutz

Levanti

Karns

et al. 2023

IJMS

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

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“…Differences were observed between mitochondria-related and ribosome-related gene expression obtained by RNAseq in this study and actual protein expression in Western blots. As noted above, this variability may be due to electrical stimulation conditions, muscle sampling for analysis, and timing of analysis 35 . In addition, differences in translation efficiency, which are not visible in mRNA abundance measurements, contribute significantly to the dynamic range of gene expression, and protein-level measurements at the mRNA level are considered incomplete 36 , which may have led to the results of this study.…”

Section: Discussionmentioning

confidence: 99%

Belt electrode tetanus muscle stimulation reduces denervation-induced atrophy of rat multiple skeletal muscle groups

Uno,

Kamiya,

Akimoto

et al. 2024

Sci Rep

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

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Changes of Gene Expression Patterns of Muscle Pathophysiology-Related Transcription Factors During Denervated Muscle Atrophy

Cited by 12 publications

References 93 publications

Opposing gene regulatory programs governing myofiber development and maturation revealed at single nucleus resolution

Opposing gene regulatory programs governing myofiber development and maturation revealed at single nucleus resolution

Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy

Belt electrode tetanus muscle stimulation reduces denervation-induced atrophy of rat multiple skeletal muscle groups

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