Watt Matthew J, Steinberg Gregory R, Heigenhauser G J F, Spriet Lawrence L, Dyck David J
School of Medical Sciences, Royal Melbourne Institute of Technology, PO Box 71, Bundoora, Victoria 3083, Australia.
Am J Physiol Endocrinol Metab. 2003 Aug;285(2):E412-9. doi: 10.1152/ajpendo.00023.2003. Epub 2003 May 20.
Cyclopiazonic acid (CPA) is a sarcoplasmic reticulum Ca2+-ATPase inhibitor that increases intracellular calcium. The role of CPA in regulating the oxidation and esterification of palmitate, the hydrolysis of intramuscular lipids, and the activation of hormone-sensitive lipase (HSL) was examined in isolated rat soleus muscles at rest. CPA (40 micro M) was added to the incubation medium to levels that resulted in subcontraction increases in muscle tension, and lipid metabolism was monitored using the previously described pulse-chase procedure. CPA did not alter the cellular energy state, as reflected by similar muscle contents of ATP, phosphocreatine, free AMP, and free ADP. CPA increased total palmitate uptake into soleus muscle (11%, P < 0.05) and was without effect on palmitate oxidation. This resulted in greater esterification of exogenous palmitate into the triacylglycerol (18%, P < 0.05) and phospholipid (89%, P < 0.05) pools. CPA decreased (P < 0.05) intramuscular lipid hydrolysis, and this occurred as a result of reduced HSL activity (20%, P < 0.05). Incubation of muscles with 3 mM caffeine, which is also known to increase Ca2+ without affecting the cellular energy state, reduced HSL activity (24%, P < 0.05). KN-93, a calcium/calmodulin-dependent kinase inhibitor (CaMKII), blocked the effects of CPA and caffeine, and HSL activity returned to preincubation values. The results of the present study demonstrate that CPA simultaneously decreases intramuscular triacylglycerol (IMTG) hydrolysis and promotes lipid storage in isolated, intact soleus muscle. The decreased IMTG hydrolysis is likely mediated by reduced HSL activity, possibly via the CaMKII pathway. These responses are not consistent with the increased hydrolysis and decreased esterification observed in contracting muscle when substrate availability and the hormonal milieu are tightly controlled. It is possible that more powerful signals or a higher [Ca2+] may override the lipid-storage effect of the CPA-mediated effects during muscular contractions.
环匹阿尼酸（CPA）是一种肌浆网Ca2 + -ATP酶抑制剂，可增加细胞内钙含量。本研究在离体的静息大鼠比目鱼肌中，检测了CPA在调节棕榈酸氧化和酯化、肌内脂质水解以及激素敏感性脂肪酶（HSL）激活方面的作用。将CPA（40微摩尔）添加到孵育培养基中，使其达到导致肌肉张力亚收缩增加的水平，并使用先前描述的脉冲追踪程序监测脂质代谢。CPA并未改变细胞能量状态，这可通过ATP、磷酸肌酸、游离AMP和游离ADP的相似肌肉含量反映出来。CPA增加了比目鱼肌对总棕榈酸的摄取（11%，P < 0.05），且对棕榈酸氧化无影响。这导致外源性棕榈酸更多地酯化到三酰甘油（18%，P < 0.05）和磷脂（89%，P < 0.05）池中。CPA降低了（P < 0.05）肌内脂质水解，这是由于HSL活性降低（20%，P < 0.05）所致。用3 mM咖啡因孵育肌肉，已知其也能增加Ca2 + 且不影响细胞能量状态，这降低了HSL活性（24%，P < 0.05）。钙/钙调蛋白依赖性激酶抑制剂（CaMKII）KN-93阻断了CPA和咖啡因的作用，HSL活性恢复到孵育前的值。本研究结果表明，CPA同时降低了离体完整比目鱼肌中的肌内三酰甘油（IMTG）水解并促进脂质储存。IMTG水解减少可能是由HSL活性降低介导的，可能是通过CaMKII途径。当底物可用性和激素环境受到严格控制时，这些反应与收缩肌肉中观察到的水解增加和酯化减少不一致。在肌肉收缩过程中，可能有更强的信号或更高的[Ca2 + ]会抵消CPA介导效应的脂质储存作用。
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