Balasubramaniam Ambikaipakan, Sheriff Sulaiman, Friend Lou Ann, James J Howard
Department of Surgery, University of Cincinnati Medical Center , Cincinnati, Ohio.
Shriner's Hospital for Children , Cincinnati, Ohio.
Am J Physiol Regul Integr Comp Physiol. 2018 Aug 1;315(2):R429-R433. doi: 10.1152/ajpregu.00042.2018. Epub 2018 Apr 25.
The phosphodiesterase 4 (PDE4)-cAMP pathway plays a predominant role in mediating skeletal muscle proteolysis in burn injury. The present investigations to determine the PDE4 isoform(s) involved in this action revealed that burn injury increased the expression of rat skeletal muscle PDE4B mRNA by sixfold but had little or no effect on expression of other PDE4 isoforms. These observations led us to study the effects of burn in PDE4B knockout (KO) rats. As reported by us previously, burn injury significantly increased extensor digitorum longus (EDL) muscle total and myofibrillar proteolysis in wild-type (WT) rats, but there were no significant effects on either total or myofibrillar protein breakdown in EDL muscle of PDE4B KO rats with burn injury. Moreover, burn injury increased PDE4 activity in the skeletal muscle of WT rats, but this was reduced by >80% in PDE4B KO rats. Also, burn injury decreased skeletal muscle cAMP concentration in WT rats but had no significant effects in the muscles of PDE4B KO rats. Incubation of the EDL muscle of burn-PDE4B KO rats with an inhibitor of the exchange factor directly activated by cAMP, but not with a protein kinase A inhibitor, eliminated the protective effects of PDE4B KO on EDL muscle proteolysis and increased muscle proteolysis to the same extent as in the EDL of burn-WT rats. These novel findings confirm a major role for PDE4B in skeletal muscle proteolysis in burn injury and suggest that an innovative therapy based on PDE4B-selective inhibitors could be developed to treat skeletal muscle cachexia in burn injury without the fear of causing emesis, which is associated with PDE4D inhibition.
磷酸二酯酶4（PDE4）-环磷酸腺苷（cAMP）信号通路在介导烧伤后骨骼肌蛋白水解过程中起主要作用。目前关于确定参与此作用的PDE4亚型的研究表明，烧伤使大鼠骨骼肌PDE4B mRNA的表达增加了6倍，但对其他PDE4亚型的表达影响很小或没有影响。这些观察结果促使我们研究烧伤对PDE4B基因敲除（KO）大鼠的影响。如我们之前所报道，烧伤显著增加了野生型（WT）大鼠趾长伸肌（EDL）的总蛋白水解和肌原纤维蛋白水解，但对烧伤的PDE4B KO大鼠EDL肌肉的总蛋白或肌原纤维蛋白分解均无显著影响。此外，烧伤增加了WT大鼠骨骼肌中的PDE4活性，但在PDE4B KO大鼠中该活性降低了80%以上。而且，烧伤降低了WT大鼠骨骼肌中的cAMP浓度，但对PDE4B KO大鼠的肌肉没有显著影响。用cAMP直接激活的交换因子抑制剂孵育烧伤-PDE4B KO大鼠的EDL肌肉，但不用蛋白激酶A抑制剂，消除了PDE4B KO对EDL肌肉蛋白水解的保护作用，并使肌肉蛋白水解增加到与烧伤-WT大鼠EDL相同的程度。这些新发现证实了PDE4B在烧伤后骨骼肌蛋白水解中的主要作用，并表明可以开发一种基于PDE4B选择性抑制剂的创新疗法来治疗烧伤后的骨骼肌恶病质，而不用担心引起与PDE4D抑制相关的呕吐。
