AMP-activated protein kinase (AMPK)is an important regulator of diverse cellular pathways in the setting of energetic stress. Whether AMPK plays a critical role in the metabolic and functional responses to myocardial ischemia and reperfusion remains uncertain. We examined the cardiac consequences of long-term inhibition of AMPK activity in transgenic mice expressing a kinase dead (KD) form of the enzyme. The KD mice had normal fractional shortening and no heart failure, cardiac hypertrophy, or fibrosis, although the in vivo left ventricular (LV) dP/dt was lower than that in WT hearts. During low-flow ischemia and postischemic reperfusion in vitro, KD hearts failed to augment glucose uptake and glycolysis, although glucose transporter content and insulin-stimulated glucose uptake were normal. KD hearts also failed to increase fatty acid oxidation during reperfusion. Furthermore, KD hearts demonstrated significantly impaired recovery of LV contractile function during postischemic reperfusion that was associated with a lower ATP content and increased injury compared with WT hearts. Caspase-3 activity and TUNEL-staining were increased in KD hearts after ischemia and reperfusion. Thus, AMPK is responsible for activation of glucose uptake and glycolysis during low-flow ischemia and plays an important protective role in limiting damage and apoptotic activity associated with ischemia and reperfusion in the heart.

Oxidative tissues such as heart undergo a dramatic perinatal mitochondrial biogenesis to meet the high-energy demands after birth. −/− mice also exhibited a severe abnormality in function and mitochondrial density. We conclude that PGC-1␣ and PGC-1␤ share roles that collectively are necessary for the postnatal metabolic and functional maturation of heart and BAT.[Keywords: Transcriptional regulation; heart development; mitochondria; energy metabolism] Supplemental material is available at http://www.genesdev.org.

The transcriptional coactivator peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣) has been identified as an inducible regulator of mitochondrial function. Skeletal muscle PGC-1␣ expression is induced post-exercise. Therefore, we sought to determine its role in the regulation of muscle fuel metabolism. Studies were performed using conditional, musclespecific, PGC-1␣ gain-of-function and constitutive, generalized, loss-of-function mice. Forced expression of PGC-1␣ increased muscle glucose uptake concomitant with augmentation of glycogen stores, a metabolic response similar to postexercise recovery. Induction of muscle PGC-1␣ expression prevented muscle glycogen depletion during exercise. Conversely, PGC-1␣-deficient animals exhibited reduced rates of muscle glycogen repletion post-exercise. PGC-1␣ was shown to increase muscle glycogen stores via several mechanisms including stimulation of glucose import, suppression of glycolytic flux, and by down-regulation of the expression of glycogen phosphorylase and its activating kinase, phosphorylase kinase ␣. These findings identify PGC-1␣ as a critical regulator of skeletal muscle fuel stores.Glucose and fatty acids are the chief fuel sources for skeletal muscle. During prolonged bouts of low intensity exercise, muscle energy needs are met through utilization of both substrates with mitochondrial fatty acid oxidation serving a "glucose sparing" function (1, 2). During acute high intensity exercise, glucose derived from hepatic and muscle glycogen stores serves as the chief energy source (reviewed in Refs. 3-5). Rapid glycogen repletion following a bout of exhausting intense exercise is an important adaptive response, preparing the muscle for subsequent bouts of activity. With endurance exercise training, the capacity for mitochondrial oxidation of fatty acids is augmented and muscle glycogen reserves increase (2). In disease states such as diabetes and heart failure, the capacity for muscle energy substrate utilization is reduced due to alterations in glucose metabolism and derangements in mitochondrial function (6, 7) (reviewed in Ref. 8).The molecular regulatory mechanisms involved in the control of muscle fuel metabolism are incompletely understood. Recent evidence implicates the transcriptional coactivator, peroxisome proliferator-activated receptor (PPAR) 5 -␥ coactivator 1␣ (PGC-1␣), in the regulation of striated muscle energy metabolism and function (9 -13). PGC-1␣ levels are rapidly induced in skeletal muscle following bouts of activity in rodents and humans (14 -22). PGC-1␣ coactivates multiple transcription factors involved in mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation, including the estrogen-related receptor ␣, PPAR␣, and nuclear respiratory factors 1 and 2 (6, 23-26). PGC-1␣ gain-and loss-of-function studies conducted in cells and in mice have demonstrated that PGC-1␣ stimulates gene regulatory programs that augment mitochondrial oxidative capacity in tissues with high energy demands, such as heart and ske...

A high peak serum glucose level during cardiopulmonary bypass is an independent risk factor for death and morbidity in diabetic patients and unexpectedly also in nondiabetic patients.

SUMMARY Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α−/−βf/f/MLC-Cre mice) were generated and characterized. PGC-1α−/−βf/f/MLC-Cre mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α−/−βf/f/MLC-Cre mice was associated with a marked diminution in muscle respiratory capacity and mitochondrial structural derangements consistent with fusion/fission and biogenic defects together with rapid depletion of muscle glycogen stores during exercise. Surprisingly, the skeletal muscle fiber type profile of the PGC-1α−/−βf/f/MLC-Cre mice was not significantly different than the wild-type mice. Moreover, insulin sensitivity and glucose tolerance were not altered in the PGC-1α−/−βf/f/MLC-Cre mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity.

Alcohol and ketogenic diets increase water consumption. Here, we show that the hormone FGF21 is required for this drinking response in mice. Circulating levels of FGF21 are increased by alcohol consumption in humans and by both alcohol and ketogenic diets in mice. Pharmacologic administration of FGF21 stimulates water drinking behavior in mice within 2 hr. Concordantly, mice lacking FGF21 fail to increase water intake in response to either alcohol or a ketogenic diet. The effect of FGF21 on drinking is mediated in part by SIM1-positive neurons of the hypothalamus and is inhibited by β-adrenergic receptor antagonists. Given that FGF21 also is known to suppress alcohol intake in favor of pure water, this work identifies FGF21 as a fundamental neurotropic hormone that governs water balance in response to specific nutrient stresses that can cause dehydration.

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Osteoclasts are responsible for bone destruction in degenerative, inflammatory and metastatic bone disorders. Although osteoclastogenesis has been well-characterized in mouse models, many questions remain regarding the regulation of osteoclast formation in human diseases. We examined the regulation of human precursors induced to differentiate and fuse into multinucleated osteoclasts by receptor activator of nuclear factor kappa-B ligand (RANKL). High-content single cell microscopy enabled the time-resolved quantification of both the population of monocytic precursors and the emerging osteoclasts. We observed that prior to induction of osteoclast fusion, RANKL stimulated precursor proliferation, acting in part through an autocrine mediator. Cytokines secreted during osteoclastogenesis were resolved using multiplexed quantification combined with a Partial Least Squares Regression model to identify the relative importance of specific cytokines for the osteoclastogenesis outcome. Interleukin 8 (IL-8) was identified as one of RANKL-induced cytokines and validated for its role in osteoclast formation using inhibitors of the IL-8 cognate receptors CXCR1 and CXCR2 or an IL-8 blocking antibody. These insights demonstrate that autocrine signaling induced by RANKL represents a key regulatory component of human osteoclastogenesis.