Cholesterol-Lowering Treatment Suppresses Neuromuscular Transmission Via Presynaptic Mechanism at the Mouse Diaphragm Muscle

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Guzel F. Zakyrjanova, Andrei N. Tsentsevitsky, Valeriya A. Matigorova, Nikita S. Fedorov, Julia G. Odnoshivkina, Guzel V. Sibgatullina, Eva A. Kapliukhina, Arthur R. Giniatullin, Arthur N. Khaziev, Artem I. Malomouzh, Yuri V. Gogolev, Alexey M Petrov
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Abstract

Statins are widely prescribed and effective cholesterol-lowering drugs for the therapy of cerebrovascular and cardiovascular disorders. The main side effects limiting statin use are muscle-related adverse events, including weakness and myopathy. The precise mechanisms of statin-induced muscle damage remain to be elucidated. Possible alterations in neuromuscular transmission might contribute to the statin side effects. Here, we studied the action of one-month treatment with atorvastatin, the most prescribed statin, on the functioning of neuromuscular junctions and related processes in the mouse diaphragm. We found that atorvastatin treatment decreases evoked acetylcholine (ACh) release and involvement of synaptic vesicles in exocytosis during intense nerve activation, as well as recovery of ACh release after tetanic stimulation. This was accompanied by increased immunolabeling of synapsin 1, a protein retaining synaptic vesicles in a non-active pool, and decreased non-quantal ACh release under resting conditions. Additionally, atorvastatin administration decreased perimeters of postsynaptic ACh receptor clusters without signs of muscle denervation. Diaphragm contractile responses to phrenic nerve stimulation at moderate-to-high frequencies and peak inspiratory flow, an indicator of diaphragm function in vivo, were decreased in atorvastatin-treated mice, whereas diaphragm contractions elicited by direct stimulation of muscle fibers were unchanged. Thus, atorvastatin treatment caused a decline in evoked ACh release and synaptic vesicle recruitment into neurotransmission that could lead to a reduction of diaphragm contractile responses to phrenic nerve activity and peak inspiratory flow. These alterations, in combination with decreased non-quantal ACh release and neuromuscular junction size, may contribute to statin-associated muscle symptoms.

Abstract Image

Abstract Image

降胆固醇治疗通过小鼠膈肌突触前机制抑制神经肌肉传递
他汀类药物被广泛用于治疗脑血管和心血管疾病,是一种有效的降胆固醇药物。限制他汀类药物使用的主要副作用是与肌肉有关的不良事件,包括无力和肌病。他汀类药物引起肌肉损伤的确切机制仍有待阐明。神经肌肉传导的可能改变可能导致他汀类药物的副作用。在这里,我们研究了阿托伐他汀(最常用的他汀类药物)治疗一个月对小鼠膈肌神经肌肉连接和相关过程功能的作用。我们发现,阿托伐他汀治疗减少了神经强烈激活时乙酰胆碱(ACh)的释放和突触囊泡参与胞吐,以及破伤风刺激后ACh释放的恢复。这伴随着突触蛋白1(一种在非活性池中保留突触囊泡的蛋白)免疫标记的增加,以及静息条件下非定量乙酰胆碱释放的减少。此外,阿托伐他汀可减少突触后ACh受体簇的周长,且无肌肉去神经支配的迹象。在阿托伐他汀治疗的小鼠中,膈神经在中高频率刺激下的膈肌收缩反应和呼气流量(体内膈肌功能的一个指标)减弱,而直接刺激肌纤维引起的膈肌收缩没有变化。因此,阿托伐他汀治疗导致诱发的乙酰胆碱释放和突触囊泡募集到神经传递的减少,这可能导致膈神经活动和吸气流量峰值的膈肌收缩反应减少。这些改变,加上非定量乙酰胆碱释放和神经肌肉连接处大小的减少,可能导致他汀类药物相关的肌肉症状。
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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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