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首页> 外文期刊>Journal of Cachexia, Sarcopenia and Muscle >Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin-induced cachexia
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Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin-induced cachexia

机译：生长激素促分泌素可防止顺铂诱导的恶病质大鼠模型骨骼肌钙稳态失调

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Abstract Background Cachexia is a wasting condition associated with cancer types and, at the same time, is a serious and dose-limiting side effect of cancer chemotherapy. Skeletal muscle loss is one of the main characteristics of cachexia that significantly contributes to the functional muscle impairment. Calcium-dependent signaling pathways are believed to play an important role in skeletal muscle decline observed in cachexia, but whether intracellular calcium homeostasis is affected in this situation remains uncertain. Growth hormone secretagogues (GHS), a family of synthetic agonists of ghrelin receptor (GHS-R1a), are being developed as a therapeutic option for cancer cachexia syndrome; however, the exact mechanism by which GHS interfere with skeletal muscle is not fully understood. Methods By a multidisciplinary approach ranging from cytofluorometry and electrophysiology to gene expression and histology, we characterized the calcium homeostasis in fast-twitch extensor digitorum longus (EDL) muscle of adult rats with cisplatin-induced cachexia and established the potential beneficial effects of two GHS (hexarelin and JMV2894) at this level. Additionally, in vivo measures of grip strength and of ultrasonography recordings allowed us to evaluate the functional impact of GHS therapeutic intervention. Results Cisplatin-treated EDL muscle fibres were characterized by a ~18% significant reduction of the muscle weight and fibre diameter together with an up-regulation of atrogin1 / Murf-1 genes and a down-regulation of Pgc1-a gene, all indexes of muscle atrophy, and by a two-fold increase in resting intracellular calcium, [Ca 2+ ] i , compared with control rats. Moreover, the amplitude of the calcium transient induced by caffeine or depolarizing high potassium solution as well as the store-operated calcium entry were ~50% significantly reduced in cisplatin-treated rats. Calcium homeostasis dysregulation parallels with changes of functional ex vivo (excitability and resting macroscopic conductance) and in vivo (forelimb force and muscle volume) outcomes in cachectic animals. Administration of hexarelin or JMV2894 markedly reduced the cisplatin-induced alteration of calcium homeostasis by both common as well as drug-specific mechanisms of action. This effect correlated with muscle function preservation as well as amelioration of various atrophic indexes, thus supporting the functional impact of GHS activity on calcium homeostasis. Conclusions Our findings provide a direct evidence that a dysregulation of calcium homeostasis plays a key role in cisplatin-induced model of cachexia gaining insight into the etiopathogenesis of this form of muscle wasting. Furthermore, our demonstration that GHS administration efficaciously prevents cisplatin-induced calcium homeostasis alteration contributes to elucidate the mechanism of action through which GHS could potentially ameliorate chemotherapy-associated cachexia.
机译：摘要背景恶病质是一种与癌症类型相关的消瘦病，同时也是癌症化学治疗的严重且剂量受限的副作用。骨骼肌丢失是恶病质的主要特征之一，恶病质显着导致功能性肌肉损伤。钙依赖的信号通路被认为在恶病质中观察到的骨骼肌衰退中起重要作用，但是在这种情况下是否影响细胞内钙稳态仍是不确定的。生长激素促分泌素（GHS）是生长素释放肽受体（GHS-R1a）的合成激动剂家族，目前正被开发为癌症恶病质综合征的治疗选择。然而，GHS干扰骨骼肌的确切机制尚不完全清楚。方法通过从细胞荧光法，电生理学到基因表达及组织学的多学科方法，我们表征了成年大鼠顺铂诱导的恶病质快速抽搐伸指长肌（EDL）肌肉中的钙稳态，并确定了两种GHS（ hexarelin和JMV2894）。此外，体内对握力的强度和超声记录的测量值使我们能够评估GHS治疗干预的功能影响。结果顺铂处理的EDL肌肉纤维的特征是肌肉重量和纤维直径显着减少了18％，同时atrogin1 / Murf-1基因上调和Pgc1-a基因下调，所有这些指标与对照组相比，肌肉萎缩，以及静止的细胞内钙[Ca 2+] i增加了两倍。此外，在顺铂治疗的大鼠中，咖啡因或去极化高钾溶液诱导的钙瞬变幅度以及储藏操作的钙进入均显着降低了约50％。钙稳态失调与恶病质动物体内离体功能变化（兴奋性和静息宏观电导）和体内变化（前肢力量和肌肉体积）平行。施用六氢可瑞林或JMV2894可通过常见以及药物特异性作用机制显着减少顺铂诱导的钙稳态的改变。这种作用与肌肉功能的保持以及各种萎缩指标的改善有关，因此支持了GHS活性对钙稳态的功能影响。结论我们的发现提供了直接的证据，表明钙稳态的失调在顺铂诱导的恶病质模型中起关键作用，从而深入了解这种形式的肌肉萎缩的病因。此外，我们的GHS给药有效预防顺铂诱导的钙稳态改变的证明有助于阐明GHS可能通过其减轻化学疗法相关的恶病质的作用机制。

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