Lidocaine Inhibits Myoblast Cell Migration and Myogenic Differentiation Through Activation of the Notch Pathway

Ling, Xiangtian; Ma, Xinqi; Kuang, Xiaying; Zou, Yuxiu; Zhang, Han; Tang, Hongfeng; Du, Han; Zhu, Binbin; Huang, Hao; Xia, Qing; Chen, Minghao; Mao, Danyi; Chen, Dongli; Shen, Huangxuan; Yan, Jianhua

doi:10.2147/dddt.s290002

Cited by 5 publications

(3 citation statements)

References 32 publications

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“…Local anesthetics may induce myotoxicity; the higher the concentrations and the longer the duration of exposure to local anesthetics, the greater the damage to the muscles. [2][3][4] Clinically relevant local anesthetics concerning myotoxicity included lidocaine, ropivacaine, and bupivacaine, in increasing order of toxicity. The addition of epinephrine to local anesthetics may also increase myotoxicity.…”

Section: Myotoxicitymentioning

confidence: 99%

Cytotoxicity of Local Anesthetics on Bone, Joint, and Muscle Tissues: A Narrative Review of the Current Literature

Zhang¹,

Li²,

Yao³

et al. 2023

JPR

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Background:Local anesthetics are commonly used in surgical procedures to control pain in patients. Whilst the cardiotoxicity and neurotoxicity of local anesthetics have received much attention, the cytotoxicity they exert against bone, joint, and muscle tissues has yet to be well recognized. Objective: This review aimed to raise awareness regarding how local anesthetics may cause tissue damage and provide a deeper understanding of the mechanisms of local anesthetic-induced cytotoxicity. We summarized the latest progress on the cytotoxicity of local anesthetics and the underlying mechanisms and discussed potential strategies to reduce it. Findings: We found that the toxic effects of local anesthetics on bone, joint, and muscle tissues were time-and concentrationdependent in vitro. Local anesthetics induced apoptosis, necrosis, and autophagy through specific cellular pathways. Altogether, this review indicates that toxicity of local anesthetics may be avoided by rationally selecting the appropriate anesthetic, limiting the total amount, and determining the lowest effective concentration and duration.

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Section: Myotoxicitymentioning

confidence: 99%

Cytotoxicity of Local Anesthetics on Bone, Joint, and Muscle Tissues: A Narrative Review of the Current Literature

Zhang¹,

Li²,

Yao³

et al. 2023

JPR

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“…A study indicated that corticosteroids prevent migration of tenocytes and are associated with decreased α‐SM expression 15 . Lidocaine has been reported to significantly mitigate platelet‐rich plasma's beneficial effects on tenocytes and inhibit the migration of myoblasts 16,17 …”

Section: Introductionmentioning

confidence: 99%

“…15 Lidocaine has been reported to significantly mitigate platelet-rich plasma's beneficial effects on tenocytes and inhibit the migration of myoblasts. 16,17 Tendon injury healing occurs in three stages: the inflammation stage, the regeneration stage, and the remodeling and maturation stage. 2 In the first of these stages, tenocytes infiltrate the repair site, actively and rapidly reproduce, and deposit extracellular matrix (ECM) components within affected tissue.…”

mentioning

confidence: 99%

Lidocaine inhibits migration of tenocytes by downregulating focal adhesion kinase and paxillin phosphorylation

Chang,

Chen,

et al. 2023

Journal Orthopaedic Research

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Lidocaine is the most frequently applied local infiltration anesthetic agent for treating tendinopathies. However, studies have discovered lidocaine to negatively affect tendon healing. In the current study, the molecular mechanisms and effects of lidocaine on tenocyte migration were evaluated. We treated tenocytes intrinsic to the Achilles tendons of Sprague–Dawley rats with lidocaine. The migration ability of cells was analyzed using electric cell‐substrate impedance sensing (ECIS) and scratch wound assay. We then used a microscope to evaluate the cell spread. We assessed filamentous actin (F‐actin) cytoskeleton formation through immunofluorescence staining. In addition, we used Western blot analysis to analyze the expression of phospho‐focal adhesion kinase (FAK), FAK, phospho‐paxillin, paxillin, and F‐actin. We discovered that lidocaine had an inhibitory effect on the migration of tenocytes in the scratch wound assay and on the ECIS chip. Lidocaine treatment suppressed cell spreading and changed the cell morphology and F‐actin distribution. Lidocaine reduced F‐actin formation in the tenocyte during cell spreading; furthermore, it inhibited phospho‐FAK, F‐actin, and phospho‐paxillin expression in the tenocytes. Our study revealed that lidocaine inhibits the spread and migration of tenocytes. The molecular mechanism potentially underlying this effect is downregulation of F‐actin, phospho‐FAK, and phospho‐paxillin expression when cells are treated with lidocaine.

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KLF13 restrains Dll4‐muscular Notch2 axis to improve the muscle atrophy

Yang,

Xiong,

Yang

et al. 2024

J cachexia sarcopenia muscle

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BackgroundMuscle atrophy can cause muscle dysfunction and weakness. Krüppel‐like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target.MethodsThe effects of gene knockdown and pharmacological targeting of KLF13 on skeletal muscle atrophy were investigated using cell‐based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing.ResultsIn a dexamethasone‐induced muscle atrophy mouse model, the KLF13 knockout group had decreased muscle strength (N) (1.77 ± 0.10 vs. 1.48 ± 0.16, P < 0.01), muscle weight (%) [gastrocnemius (Gas): 76.0 ± 5.69 vs. 60.7 ± 7.23, P < 0.001; tibialis anterior (TA): 75.8 ± 6.21 vs. 67.5 ± 5.01, P < 0.05], and exhaustive running distance (m) (495.5 ± 64.8 vs. 315.5 ± 60.9, P < 0.05) compared with the control group. KLF13 overexpression preserved muscle mass (Gas: 100 ± 6.38 vs. 120 ± 14.4, P < 0.01) and the exhaustive running distance (423.8 ± 59.04 vs. 530.2 ± 77.45, P < 0.05) in an in vivo diabetes‐induced skeletal muscle atrophy model. Clofoctol treatment protected against dexamethasone‐induced muscle atrophy. Myotubes treated with dexamethasone, an atrophy‐inducing glucocorticoid, were aggravated by KLF13 knockout, but anti‐atrophic effects were achieved by inducing KLF13 overexpression. We performed a transcriptome analysis and luciferase reporter assays to further explore this mechanism, finding that delta‐like 4 (Dll4) was a novel target gene of KLF13. The KLF13 transcript repressed Dll4, inhibiting the Dll4‐Notch2 axis and preventing muscle atrophy. Dexamethasone inhibited KLF13 expression by inhibiting myogenic differentiation 1 (i.e., MYOD1)‐mediated KLF13 transcriptional activation and promoting F‐Box and WD repeat domain containing 7 (i.e., FBXW7)‐mediated KLF13 ubiquitination.ConclusionsThis study sheds new light on the mechanisms underlying skeletal muscle atrophy and potential drug targets. KLF13 regulates muscle atrophy and is a potential therapeutic target. Clofoctol is an attractive compound for repurposing studies to treat skeletal muscle atrophy.

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Lidocaine Inhibits Myoblast Cell Migration and Myogenic Differentiation Through Activation of the Notch Pathway

Cited by 5 publications

References 32 publications

Cytotoxicity of Local Anesthetics on Bone, Joint, and Muscle Tissues: A Narrative Review of the Current Literature

Cytotoxicity of Local Anesthetics on Bone, Joint, and Muscle Tissues: A Narrative Review of the Current Literature

Lidocaine inhibits migration of tenocytes by downregulating focal adhesion kinase and paxillin phosphorylation

KLF13 restrains Dll4‐muscular Notch2 axis to improve the muscle atrophy

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