.32) was linked to the ␣-skeletal actin gene promoter, express PEPCK-C in skeletal muscle (1-3 units/g). Breeding two founder lines together produced mice with an activity of PEPCK-C of 9 units/g of muscle (PEPCK-C mus mice). These mice were seven times more active in their cages than controls. On a mouse treadmill, PEPCK-C mus mice ran up to 6 km at a speed of 20 m/min, whereas controls stopped at 0.2 km. PEPCK-C mus mice had an enhanced exercise capacity, with a VO 2max of 156 ؎ 8.0 ml/kg/min, a maximal respiratory exchange ratio of 0.91 ؎ 0.03, and a blood lactate concentration of 3.7 ؎ 1.0 mM after running for 32 min at a 25°grade; the values for control animals were 112 ؎ 21 ml/kg/min, 0.99 ؎ 0.08, and 8.1 ؎ 5.0 mM respectively. The PEPCK-C mus mice ate 60% more than controls but had half the body weight and 10% the body fat as determined by magnetic resonance imaging. In addition, the number of mitochondria and the content of triglyceride in the skeletal muscle of PEPCK-C mus mice were greatly increased as compared with controls. PEPCK-C mus mice had an extended life span relative to control animals; mice up to an age of 2.5 years ran twice as fast as 6 -12-month-old control animals. We conclude that overexpression of PEPCK-C repatterns energy metabolism and leads to greater longevity. PEPCK-C2 is involved in gluconeogenesis in the liver and kidney cortex and in glyceroneogenesis in liver and white and brown adipose tissue (see Ref. 1 for a review). However, this enzyme is also present in a broad variety of mammalian tissues (2), including the small intestine, colon, mammary gland, adrenal gland, lung, and muscle; its metabolic role in these tissues remains obscure. To study the physiological function of PEPCK-C, the gene has been overexpressed or ablated in specific tissues of the mouse. When PEPCK-C was overexpressed in white adipose tissue, the mice had increased rates of glyceroneogenesis in their adipose tissue and became obese (3). In contrast, ablating the expression of PEPCK-C in adipose tissue resulted in mice with lipodystrophy (4). However, a systematic study involving other mammalian tissues where the enzyme has been detected has not been undertaken.We have overexpressed the gene for PEPCK-C in the skeletal muscle of transgenic mice to test the metabolic and physiological consequences. Skeletal muscle was selected as a target organ because there is no clear indication of the metabolic outcome of having a high activity of PEPCK-C in this tissue. Skeletal muscle does not synthesize and release glucose, although there have been reports over the years that the tissue can make glycogen de novo since both PEPCK-C and fructose-1-6-bisphosphatase activities have been found in skeletal muscle (5, 6). We have evidence from research ongoing in our laboratory 3 that glyceroneogenesis occurs in skeletal muscle. This pathway is an abbreviated version of gluconeogenesis, which involves the synthesis of glycerol-3-phosphate (used for triglyceride synthesis) from precursors other than glucose and glycerol. Howe...

Abstract-This statement is an updated report of the American Heart Association's previous publications on exercise in children. In this statement, exercise laboratory requirements for environment, equipment, staffing, and procedures are presented. Indications and contraindications to stress testing are discussed, as are types of testing protocols and the use of pharmacological stress protocols. Current stress laboratory practices are reviewed on the basis of a survey of pediatric cardiology training programs.

The model has three distinct domains (blood, cytosol, and mitochondria) with interdomain transport of chemical species. In addition to distinguishing between cytosol and mitochondria, the model includes a subdomain in the cytosol to account for glycolytic metabolic channeling. Myocardial ischemia was induced by a 60% reduction in coronary blood flow, and model simulations were compared with experimental data from anesthetized pigs. Simulations with a previous model without compartmentation showed a slow activation of glycogen breakdown and delayed lactate production compared with experimental results. The addition of a subdomain for glycolysis resulted in simulations showing faster rates of glycogen breakdown and lactate production that closely matched in vivo experimental data. The dynamics of redox (NADH/NAD ϩ ) and phosphorylation (ADP/ATP) states were also simulated. These controllers are coupled to energy transfer reactions and play key regulatory roles in the cytosol and mitochondria. Simulations showed a similar dynamic response of the mitochondrial redox state and the rate of pyruvate oxidation during ischemia. In contrast, the cytosolic redox state displayed a time response similar to that of lactate production. In conclusion, this novel mechanistic model effectively predicted the rapid activation of glycogen breakdown and lactate production at the onset of ischemia and supports the concept of localization of glycolysis to a subdomain of the cytosol. redox state; computer simulation; cytosol; mitochondria; metabolic channeling THE PRIMARY EFFECT of myocardial ischemia is impaired oxidative phosphorylation due to decreased oxygen delivery to the mitochondria (68). Reduced aerobic ATP production stimulates glycogen breakdown and ATP formation from glycolysis in the cytosol and results in lactate accumulation in the tissue (52, 68). Various metabolites related to energy transfer (e.g., NADH-NAD ϩ and ADP-ATP) act as modulators of key reactions in the cytosol and mitochondria but have different concentrations in these cellular domains. For example, under aerobic conditions, 5-10% of total ATP (10, 62) and 90% of the NAD ϩ and NADH (61) are in the mitochondria. On the basis of this evidence, it is inappropriate to assume the same concentrations of these metabolites in the cytosol and mitochondria when studying mechanisms controlling glycolysis and lactate metabolism from normal to ischemic conditions. Furthermore, it has been observed that key glycolytic enzymes are bound together in specific intracellular structures to form a multienzyme complex near the sarcolemma and sarcoplasmic reticulum (8,19,42). Because the glycolytic enzymes are not freely distributed, glycolysis can be considered localized in a subdomain within the cytosol.Unfortunately, at present, it is not feasible to measure dynamic changes in the fluxes and concentrations of key cytosolic and mitochondrial species in the transition from normal to ischemic conditions with current experimental techniques. As an alternate approach to conducting e...

A mathematical model of the whole-body metabolism is developed to predict fuel homeostasis during exercise by using hormonal control over cellular metabolic processes. The whole body model is composed of seven tissue compartments: brain, heart, liver, GI (gastrointestinal) tract, skeletal muscle, adipose tissue, and "other tissues". Each tissue compartment is described by dynamic mass balances and major cellular metabolic reactions. The glucagon-insulin controller is incorporated into the whole body model to predict hormonal changes during exercise. Moderate [150 W power output at 60% of peak oxygen consumption (VO(2max))] exercise for 60 min was implemented by increasing ATP utilization rates in heart and skeletal muscle. Arterial epinephrine level was given as an input function, which directly affects heart and skeletal muscle metabolism and indirectly other tissues via glucagon-insulin controller. Model simulations were validated with experimental data from human exercise studies. The exercise induced changes in hormonal signals modulated metabolic flux rates of different tissues in a coordinated way to achieve glucose homeostasis, demonstrating the efficacy of hormonal control over cellular metabolic processes. From experimental measurements of whole body glucose balance and arterial substrate concentrations, this model could predict the dynamic changes of hepatic glycogenolysis and gluconeogenesis, which are not easy to measure experimentally, suggesting the higher contribution of glycogenolysis ( approximately 75%). In addition, it could provide dynamic information on the relative contribution of carbohydrates and lipids for fuel oxidation in skeletal muscle. Model simulations indicate that external fuel supplies from other tissue/organ systems to skeletal muscle become important for prolonged exercise emphasizing the significance of interaction among tissues. In conclusion, this model can be used as a valuable complement to experimental studies due to its ability to predict what is difficult to measure directly, and usefulness to provide information about dynamic behaviors.