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To study how sarcomere length inhomogeneities and the duration of activation affect sarcomere length-force characteristics of muscle, the mean sarcomere length-force relationship was determined for twitches and at 100 and 300 ms during tetanic activation for rat extensor digitorum longus and gastrocnemius medialis muscle fibre bundles. Mean sarcomere length is the mean length of all sarcomere within the fibre, calculated by dividing fibre length by the number of sarcomeres in series in the fibre.The twitch mean sarcomere length-force relationship is shifted to larger sarcmere lengths (optimum mean sarcomere length = 2.69 μm) compared to the relationships determined at 100 or 300 ms of tetanic activation (optimum mean sarcomere length = 2.38 μm), which were the same. It is shown that the normalized Gordon et al. rationale results in a large overestimate of force (at most 68% of force at a sarcomere length of 1.60 μm) for mean sarcomere lengths between 1.4 and 2.0 μm, and in an underestimate of force between 2.3 and 3.0 μm. It is conclude tthat modelling skeletal mammalian muscle length-force relationships can be improved by using mean sarcomere length-force relations of mammalian fibres instead of the normalized rationale of Gordon et al. derived from a selected homogeneous part of frog fibre.

Although usually steady-state fluxes and metabolite levels are assessed for the study of metabolic regulation, much can be learned from studying the transient response during quick changes of an input to the system. To this end we study the transient response of O2consumption in the heart during steps in heart rate. The time course is characterized by the mean response time of O2consumption which is the first statistical moment of the impulse response function of the system (for mono-exponential responses equal to the time constant). The time course of O2uptake during quick changes is measured with O2electrodes in the arterial perfusate and venous effluent of the heart, but the venous signal is delayed with respect to O2consumption in the mitochondria due to O2diffusion and vascular transport. We correct for this transport delay by using the mass balance of O2, with all terms (e.g. O2consumption and vascular O2transport) taken as function of time. Integration of this mass balance over the duration of the response yields a relation between the mean transit time for O2and changes in cardiac O2content. Experimental data on the response times of venous [O2] during step changes in arterial [O2] or in perfusion flow are used to calculate the transport time between mitochondria and the venous O2electrode. By subtracting the transport time from the response time measured in the venous outflow the mean response time of mitochondrial O2consumption (tmito) to the step in heart rate is obtained. In isolated rabbit heart we found that tmitoto heart rate steps is 4-12 s at 37°C. This means that oxidative phosphorylation responds to changing ATP hydrolysis with some delay, so that the phosphocreatine levels in the heart must be decreased, at least in the early stages after an increase in cardiac ATP hydrolysis. Changes in ADP and inorganic phosphate (Pi) thus play a role in regulating the dynamic adaptation of oxidative phosphorylation, although most steady state NMR measurements in the heart had suggested that ADP and Pido not change. Indeed, we found with 31P-NMR spectroscopy that phosphocreatine (PCr) and Pichange in the first seconds after a quick change in ATP hydrolysis, but remarkably they do this significantly faster (time constant ~2.5 s) than mitochondrial O2consumption (time constant 12 s). Although it is quite likely that other factors besides ADP and Piregulate cardiac oxidative phosphorylation, a fascinating alternative explanation is that the first changes in PCr measured with NMR spectroscopy took exclusively place in or near the myofibrils, and that a metabolic wave must then travel with some delay to the mitochondria to stimulate oxidative phosphorylation. The tmitoslows with falling temperature, intracellular acidosis, and sometimes also during reperfusion following ischemia and with decreased mitochondrial aerobic capacity. In conclusion, the study of the dynamic adaptation of cardiac oxidative phosphorylation to demand using the mean response time of cardiac mitochondrial O2consumption is a very valuable tool to investigate the regulation of cardiac mitochondrial energy metabolism in health and disease.

It is unclear to what extent mitochondrial functionin vivois changed after brief anoxia. Heat measurements allow evaluation of mitochondrial function within intact cardiac muscle. Heat production was determined using fast metal-film thermopiles, during contraction and post-contractile recovery in control and stunned superfused rabbit papillary muscles at 20°C. Heat rate was measured for a train of ten twitches (0.2 Hz) before anoxia and after 40 min anoxia followed by 2 h of normoxic recovery. During anoxia muscles were stimulated at 0.2 Hz (group A) or at 1.0 Hz (group B). A normoxic control group C was stimulated at 0.2 Hz. After 2 h recovery, tension was 77±5% (s.e.m.), 72±7% and 94±3% of initial values, for group A, B and C respectively, indicating stunning by anoxia. The economy of contraction or the ratio of recovery heat to initial heat did not change significantly in groups A and B when compared with control, indicating that stunning with this protocol is not associated with mitochondrial uncoupling. Post-contractile recovery heat initially decayed exponentially with time constant 24.9±2.2 s for all groups and with 22.7±1.1, 22.0±0.8 and 41.7±4.4 s at the end for group A, B and C respectively. The cause of the remarkable slowing of the recovery rate over time in controls is unknown, but is mimicked by blocking fatty acid utilization. No slowing of metabolic recovery is observed in the stunned papillary muscles. We conclude that stunning is not associated with a decrease in mitochondrial function or oxidative capacity in cardiac muscle.

In this review, the regional heterogeneity of the oxygen supply-consumption ratio within the heart is discussed. This is an important functional parameter because it determines whether regions within the heart are normoxic or dysoxic. Although the heterogeneity of the supply side of oxygen has been primarily described by flow heterogeneity, the diffusional component of oxygen supply should not be ignored, especially at high resolution (tissue regions ≪ 1 g). Such oxygen diffusion does not seem to take place from arterioles or venules within the heart, but seems to occur between capillaries, in contrast to data recently obtained from other tissues. Oxygen diffusion may even become the primary determinant of oxygen supply during obstructed flow conditions. Studies aimed at modelling regional blood flow and oxygen consumption have demonstrated marked regional heterogeneity of oxygen consumption matched by flow heterogeneity. Direct, non-invasive indicators of the balance between oxygen supply and consumption include NADH videofluorimetry (mitochondrial energy state) and microvascular PO2 measurement by the Pd-porphyrin phosphorescence technique. These indicators have shown a relatively homogeneous distribution during physiological conditions supporting the notion of regional matching of oxygen supply with oxygen consumption. NADH videofluorimetry, however, has demonstrated large increases in functional heterogeneity of this ratio in compromised hearts (ischemia, hypoxia, hypertrophy and endotoxemia) with specific areas, referred to as microcirculatory weak units, predisposed to showing the first signs of dysoxia. It has been suggested that these weak units show the largest relative reduction in flow (independent of absolute flow levels) during compromising conditions, with dysoxia initially developing at the venous end of the capillary.