G-protein-coupled receptors are thought to have an inactive conformation (R), requiring an agonist-induced conformational change for receptor/G-protein coupling. But new evidence suggests a two-state model in which receptors are in equilibrium between the inactive conformation (R), and a spontaneously active conformation (R*) that can couple to G protein in the absence of ligand (Fig. 1). Classic agonists have a high affinity for R* and increase the concentration of R*, whereas inverse agonists have a high affinity for R and decrease the concentration of R*. Neutral competitive antagonists have equal affinity for R and R* and do not displace the equilibrium, but can competitively antagonize the effects both of agonists and of inverse agonists. The lack of suitable in vivo model systems has restricted the evidence for the existence of inverse agonists to computer simulations and in vitro systems. We have used a transgenic mouse model in which there is such marked myocardial overexpression of beta 2-adrenoceptors that a significant population of spontaneously activated receptor (R*) is present, inducing a maximal response without agonist. We show that the beta 2-adrenoceptor ligand ICI-118,551 functions as an inverse agonist, providing evidence supporting the existence of inverse agonists and validating the two-state model of G-protein-coupled receptor activation.

Results: Individuals completing the 6-month program averaged a weight loss of 7.3% in men and 4.7% in women. Fasting lipids and blood glucose improved in both genders regardless of age. Outcomes including BMI and lipids improved in women regardless of menopausal status or hormone replacement therapy. There was a significant correlation between percentage weight loss and number of weekly counseling sessions attended and number of visits to the wellness center for exercise. Discussion: Participants who complete a structured community-based weight management program can achieve significant weight loss and improvement in cardiovascular risk factors regardless of age, gender, or menopausal status. Our analysis suggests that national treatment guidelines/recommendations for weight management can be effectively implemented in a community medical wellness center. The relatively high drop-out rate associated with this program suggests the need to identify strategies and techniques to enhance adherence and completion of programs.

Aging of rats results in slower activities of calcium transport by cardiac calcium adenosinetriphosphatase (ATPase) of the sarcoplasmic reticulum (SR) and mitochondrial cytochrome oxidase (COX). These enzyme activities are faster after exercise training of previously sedentary old rats. Our purpose was to determine whether the expression of the genes encoding SR calcium ATPase (SERCA2a) or COX is altered by exercise training. Old (24-mo-old) male Fischer 344 rats were assigned to SO (sedentary old) or EO (exercised old) groups and compared with younger (12-mo-old) sedentary rats (SM). EO rats were trained on a treadmill for 8-10 wk. SERCA2a and COX mRNAs were lower (P < 0.05) in SO compared with SM and EO, whereas glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and cardiac alpha-actin mRNAs were similar across groups. The immunoreactive protein contents of cardiac calcium ATPase, cytochrome c, sarcomeric actin, and GAPDH followed the changes, when observed, in mRNA contents. Thus pretranslational mechanisms may be modified in some genes during aging and exercise training of previously sedentary old rats.

In its second messenger role in skeletal muscle, calcium coordinates the function of muscle (contractile activity) with its overall energetics, thereby controlling the provision of ATP in a time of need. Not only is ATP required for crossbridge turnover in the myofibrils, but it is also needed for the maintenance of ion pumps, nuclear activity, and so forth. When oxygen is limiting, the sustained contractions of both fast and slow muscle (after the immediate burst of activity) is primarily supported by glycogenolysis and the glycolytic pathway (anaerobic). Calcium is important to this process, and the compartmentation of the glycogen particle and some of the enzymes associated with the glycolytic pathway in the terminal cisternae of the sarcoplasmic reticulum ensures that the provision of glucose-6-phosphate to the glycolytic pathway for the generation of the needed ATP proceeds rapidly. The activation of phosphorylase and glycogenolysis by calcium-troponin-C is another example of the tight control of cellular energetics deemed possible by compartmentation within the cell. The regulation by calcium, therefore, is only dependent on the diffusion of calcium rather than diffusion of substrate. When oxygen is not limiting (i.e. when a new steady-state is reached), the aerobic metabolism of pyruvate and fatty acids may be regulated in part by calcium at least in slow skeletal muscle. Oxidative phosphorylation, where ADP is phosphorylated to ATP, is though to be controlled by the concentration of ADP in skeletal muscle. However, because of the obvious compartmentation of the mitochondria within the slow muscle fibre and the higher free calcium required for peak force development (5 mumol/L), the kinetics are theoretically favourable for the calcium cycle in slow muscle mitochondria to play an important role in the regulation of aerobic substrate oxidation, as it does in the heart. Although this hypothesis is attractive based on the available data, the direct demonstration of a major role for calcium as a regulator of substrate oxidation in slow muscle awaits experimentation.