Chronic treatment with the β2-adrenoceptor agonist prodrug BRL-47672 impairs rat skeletal muscle function by inducing a comprehensive shift to a faster muscle phenotype
Chronic treatment with the β2-adrenoceptor agonist prodrug BRL-47672 impairs rat skeletal muscle function by inducing a comprehensive shift to a faster muscle phenotype
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DOI：
10.1124/jpet.106.107045
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发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Greenhaff, Paul L.
中科院分区：
文献类型：
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作者：
Baker, David J.;Constantin-Teodosiu, D.;Greenhaff, Paul L.
发现维持或改善恶病质、术后无力和肌肉减少症患者肌肉功能（抗疲劳性）的方法具有临床重要性。β（2）-激动剂治疗增加了肌肉质量，但它改变了纤维比例，因此对肌肉功能的净影响仍不清楚。在本研究中，我们重点关注β 2受体激动剂前药BRL-47672（BRL）长期治疗的收缩和代谢结果。腓肠肌-跖肌（GPS）肌肉在休息和研究疲劳特性的四肢模型。BRL治疗使GPS质量增加了21%（P < 0.05），而在20秒的收缩期间出现了更大的疲劳（减少了45%的工作; P < 0.05）。在表型上，BRL导致11b型肌球蛋白重链蛋白表达增加17%（P < 0.001），并且在20 s收缩期间腺嘌呤核苷酸的释放增加（P < 0.05）。慢性BRL治疗使最大脂质氧化能力降低30%（P < 0.05），谷氨酸脱氢酶活性降低15%（P < 0.05）。我们得出结论，β 2受体激动剂诱导的肌肉肥大可能是临床上有限的，因为能量代谢和功能受损，可能是肌肉表型转变的结果。
Discovering approaches to maintain or improve muscle function (fatigue resistance) in patients with cachexia, postoperative weakness, and sarcopenia is of clinical importance. beta(2)-Agonist treatment increases muscle mass, yet it alters fiber proportions such that the net consequences on muscle function remain unclear. In the present study, we focus on the contractile and metabolic consequences of chronic treatment with the beta(2)-agonist prodrug BRL-47672 (BRL). Gastrocnemius-plantarissoleus (GPS) muscles were harvested at rest and studied for fatigue characteristics during 4 limb model. BRL treatment increased GPS mass by 21% (P < 0.05), whereas greater fatigue occurred during 20 s of contraction (45% less work; P < 0.05). Phenotypically, BRL resulted in 17% more type llb myosin heavy chain protein expression (P < 0.001) and greater adenine nucleotide catabolism during 20 s of contraction (P < 0.05). Chronic BRL treatment impaired maximal lipid oxidation capacity by 30% (P < 0.05) and reduced glutamate dehydrogenase activity by 15% (P < 0.05). We conclude that beta(2)-agonist induced muscle hypertrophy may be clinically limited as impaired energy metabolism and function occur, presumably as a consequence of the shift in muscle phenotype.