Cell-attached patch-clamp recordings on native striated myofibers from adult dystrophic mdx mice revealed a higher occurrence and open probability compared to non-dystrophic wild-type myofibers of a 30 pS voltage-insensitive Ca2+-permeable channel, inhibited by Gd3+, streptomycin and ruthenium red. Myofibers from in vivo exercised animals had higher channel occurrence and/or open probability. Insulin-like growth factor 1 (3.3 nM) induced and/or enhanced channel activity, via PI3 kinase, in wild-type but not in mdx myofibers. Interestingly, in both genotypes the current was silenced by db-cAMP or pentoxifylline, a phosphodiesterase inhibitor. The channel activity/occurrence in pentoxifylline-treated exercised mdx (50 mg/kg/day i.p. for 4-8 weeks) overlapped that of exercised wild-type mice. Thus, a growth factor-sensitive current, likely due to a TRP channel, is activated in vivo by exercise in native striated fibers; its deregulation in the absence of dystrophin may contribute to Ca2+ homeostasis alteration. The possibility to pharmacologically counteract abnormal channel activity discloses important therapeutic application.

译文

成年营养不良mdx小鼠的天然横纹肌纤维上的细胞附着膜片钳记录显示,与30 ps电压不敏感的Ca2渗透通道的非营养不良野生型肌纤维相比,其发生的可能性和开放的可能性更高,受到Gd3,链霉素和钌的抑制红。来自体内运动动物的肌纤维具有更高的通道发生和/或开放概率。胰岛素样生长因子1 (3.3纳米) 通过PI3激酶在野生型但在mdx肌纤维中诱导和/或增强通道活性。有趣的是,在两种基因型中,电流均被磷酸二酯酶抑制剂db-cAMP或己酮可可碱沉默。己酮可可碱处理的运动mdx (50 mg/kg/天,每天腹腔注射4-8周) 的通道活性/发生与运动野生型小鼠的通道活性/发生重叠。因此,可能是由于TRP通道引起的对生长因子敏感的电流在体内通过在天然横纹纤维中的运动而被激活; 在没有肌营养不良蛋白的情况下,其失调可能会导致Ca2稳态改变。从药理学上消除异常通道活性的可能性揭示了重要的治疗应用。

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