Hardie. Effects of endurance training on activity and expression of AMP-activated protein kinase isoforms in rat muscles. Am J Physiol Endocrinol Metab 283: E178-E186, 2002. First published March 12, 2002 10.1152/ajpendo.00404.2001.-The effects of endurance training on the response of muscle AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) to moderate treadmill exercise were examined. In red quadriceps, there was a large activation of ␣2-AMPK and inactivation of ACC in response to exercise. This response was greatly reduced after training, probably because of reduced metabolic stress. In white quadriceps, there were no effects of exercise on AMPK or ACC, but ␣2-activity was higher after training because of increased phosphorylation of Thr 172 . In soleus, there were small increases in ␣2-activity during exercise that were not affected by training. The expression of all seven AMPK subunit isoforms was also examined. The ␤2-and ␥2-isoforms were most highly expressed in white quadriceps, and ␥3 was expressed in red quadriceps and soleus. There was a threefold increase in expression of ␥3 after training in red quadriceps only. Our results suggest that ␥3 might have a special role in the adaptation to endurance exercise in muscles utilizing oxidative metabolism.

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The four R-spondins (RSPO1-4) strongly potentiate Wnt signaling and play critical roles in normal development, adult stem cell survival, and cancer development and aggressiveness. All four RSPOs have been suggested to potentiate Wnt signaling by binding to three related receptors, leucine-rich repeat-containing, G protein-coupled receptors 4, 5, and 6 (LGR4/5/6), and then inducing the clearance of two E3 ubiquitin ligases (RNF43 and ZNRF3) that otherwise would ubiquitinate Wnt receptors for degradation. Here, we show that RSPO1-4 have differential dependence on LGRs in potentiating Wnt/β-catenin signaling and that RSPO2 can enhance this pathway without any LGR. LGR4 knockout (LGR4KO) in HEK293 cells completely abrogated the Wnt/β-catenin signaling response to RSPO1 and RSPO4 and strongly impaired the response to RSPO3. RSPO2, however, retained robust activity albeit with decreased potency. Complete rescue of RSPO1-4 activity in LGR4KO cells required the seven-transmembrane domain of LGR4. Furthermore, an RSPO2 mutant with normal binding affinity to ZNRF3 but no or little binding to LGR4 or LGR5 still potentiated Wnt/β-catenin signaling, supported the growth of intestinal organoids , and stimulated intestinal crypt growth Mechanistically, RSPO2 could increase Wnt receptor levels in the absence of any LGR without affecting ZNRF3 endocytosis and stability. These findings suggest that RSPO1-4 use distinct mechanisms in regulating Wnt and other signaling pathways, which have important implications for understanding the pleiotropic functions of RSPOs and LGRs in both normal and cancer development.

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