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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 ] , 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.

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

背景

恶病质是一种与多种癌症相关的消瘦状态，同时也是癌症化疗严重的剂量限制性副作用。骨骼肌丢失是恶病质的主要特征之一，显著导致肌肉功能受损。钙依赖性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，但在这种情况下细胞内钙稳态是否受到影响仍不确定。生长激素促分泌素（GHS）是胃饥饿素受体（GHS-R1a）的一类合成激动剂，正被开发作为癌症恶病质综合征的一种治疗选择；然而，GHS干扰骨骼肌的确切机制尚未完全了解。

方法

通过从细胞荧光测定法、电生理学到基因表达和组织学的多学科方法，我们对顺铂诱导的恶病质成年大鼠的快肌趾长伸肌（EDL）中的钙稳态进行了表征，并确定了两种GHS（六肽生长激素释放肽和JMV2894）在此水平上的潜在有益作用。此外，通过握力的体内测量和超声记录，我们能够评估GHS治疗干预的功能影响。

结果

与对照大鼠相比，顺铂处理的EDL肌纤维的特征是肌肉重量和纤维直径显著降低约18%，同时萎缩相关基因atrogin1/Murf-1上调，Pgc1-a基因下调，静息细胞内钙浓度[Ca]增加两倍。此外，顺铂处理的大鼠中，咖啡因或去极化高钾溶液诱导的钙瞬变幅度以及储存操纵性钙内流显著降低约50%。钙稳态失调与恶病质动物的离体功能变化（兴奋性和静息宏观电导率）和体内功能变化（前肢力量和肌肉体积）平行。给予六肽生长激素释放肽或JMV2894通过共同以及药物特异性作用机制显著降低了顺铂诱导的钙稳态改变。这种作用与肌肉功能的保留以及各种萎缩指标的改善相关，从而支持了GHS活性对钙稳态的功能影响。