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Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623
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ABSTRACT |
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 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
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We tested the hypothesis that contracting skeletal muscle can rapidly restore force development during reperfusion after brief total ischemia and that this rapid recovery depends on O2 availability and not an alternate factor related to blood flow. Isolated canine gastrocnemius muscle (n = 5) was stimulated to contract tetanically (isometric contraction elicited by 8 V, 0.2-ms duration, 200-ms trains, at 50-Hz stimulation) every 2 s until steady-state conditions of muscle blood flow (controlled by pump perfusion) and developed force were attained (3 min). While maintaining the same stimulation pattern, muscle blood flow was then reduced to zero (complete ischemia) for 2 min. Normal blood flow was then restored to the contracting muscle; however, two distinct conditions of oxygenation (at the same blood flow) were sequentially imposed: deoxygenated blood (30 s), blood with normal arterial O2 content (30 s), a return to deoxygenated blood (30 s), and finally a return to normal arterial O2 content (90 s). During the ischemic period, force development fell to 39 ± 6 (SE)% of normal (from 460 ± 40 to 170 ± 20 N/100 g). When muscle blood flow was restored to normal by perfusion with deoxygenated blood, developed force continued to decline to 140 ± 20 N/100 g. Muscle force rapidly recovered to 310 ± 30 N/100 g (P < 0.05) during the 30 s in which the contracting muscle was perfused with oxygenated blood and then fell again to 180 ± 30 N/100 g when perfused with blood with low PO2. These findings demonstrate that contracting skeletal muscle has the capacity for rapid recovery of force development during reperfusion after a short period of complete ischemia and that this recovery depends on O2 availability and not an alternate factor related to blood flow restoration.
fatigue; reperfusion; exercise; blood flow
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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FATIGUE, OR A REDUCTION in force output for a given stimulation, during relatively high-intensity exercise will generally occur when the demand of the ATPases exceeds the ability of the muscle to maintain ATP production through oxidative phosphorylation and substrate-level phosphorylation (26). When working muscle is made ischemic (reduction in blood flow), O2 availability to the mitochondria can become compromised, and ATP generation by oxidative phosphorylation will be inadequate for the demand of the ATPases, resulting in attenuation of developed tension. The extent of the contractile dysfunction will depend on the duration and severity of the ischemic episode. During conditions of partial ischemia, the reduction in force development is generally proportional to the reduction in O2 availability (10, 11, 15), and force generation will achieve a new steady state at which demand of the ATPases can be met by oxidative metabolism.
The recovery of force production after a fatiguing bout of high-intensity exercise follows a time course that is partially dependent on the restoration of homeostatic conditions in the intracellular environment (6, 27). There is some evidence that, if a brief ischemic period is imposed in the midst of steady-state skeletal muscle contractions, subsequent blood flow reperfusion during the contractile period can result in some degree of recovery in force development (12, 18), demonstrating that the "fatigue" process under these conditions may be rapidly reversible. The factors that allow recovery of muscle function on reperfusion after an episode of brief blood flow cessation are not well understood. Whereas recovery of force development after a period of brief ischemia will certainly be dependent on restoration of blood flow, it remains unclear whether it is the reinstatement of O2 availability or some other factor related to blood flow [associated with either delivery of a substrate(s) other than O2 or removal of metabolic waste products trapped in the tissue] that may result in a potentially rapid recovery of force development.
The purpose of the present study was to test the hypothesis that contracting skeletal muscle has the capacity to rapidly restore force generation on blood flow reperfusion after a period of brief total ischemia and that this process is dependent on the reestablishment of O2 availability and not an alternate factor(s) related to blood flow reinstatement.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Adult female mongrel dogs (n = 5) with a weight range of 15-20 kg were anesthetized with 30 mg/kg pentobarbital sodium, and maintenance doses were given as required. Heparin was given to the animals at a dosage of 1,500 U/kg after the surgery described below. Ventilation was maintained with a Harvard 613 ventilator to keep blood gases and pH normal. These experiments were approved by the animal subjects committee at the University of California, San Diego.
Surgical preparation. The left gastrocnemius-flexor digitorum superficialis muscle complex (for convenience referred to as gastrocnemius) was isolated as described previously (19). All vessels draining into the popliteal vein, except for those from the gastrocnemius, were ligated to isolate the venous outflow. The arterial circulation to the gastrocnemius was isolated by ligating all vessels from the femoral and popliteal artery that did not enter the gastrocnemius. The left popliteal vein was cannulated, and the venous outflow was returned to the animal via a jugular catheter. A blood flowmeter (T108, Transonic Systems) was inserted in this line to monitor muscle blood flow.
The right femoral artery was catheterized for arterial blood sampling. This catheter was connected to the left femoral artery so that the isolated muscle was perfused by blood from this contralateral artery. Perfusion was accomplished via a Sigmamotor pump to control flow. A pressure transducer in this line at the head of the muscle constantly monitored perfusion pressure. The left sciatic nerve, which innervates the gastrocnemius, was doubly ligated and cut between ties. To prevent cooling and drying, all exposed tissues were covered with saline-soaked gauze and with a sheet of plastic. After the muscle was surgically isolated, the Achilles tendon was attached to an isometric myograph (SM-100, Interface Electronics) to measure tension development. The hindlimb was fixed at the knee and ankle and attached to the myograph with struts to minimize movement. Weights were used at the end of each experiment to calibrate the tension myograph.Experimental protocol. Before the experimental protocol was commenced, each animal inhaled 100% N2 for 2-3 min. At the end of this time period, 200 ml of blood with low PO2 were quickly withdrawn from the animal. This blood was kept well stirred in a sealed beaker at a temperature of 37°C and gently bubbled with a gas mixture of 95% N2 and 5% CO2 until it was used 15-20 min later for the deoxygenated treatment. A line from this beaker was run to a three-way valve at the perfusion pump so that the blood being pumped to the muscle could be quickly switched from the normal arterial blood of the dog to the deoxygenated blood contained within the sealed beaker. The pump perfusing the muscle was positioned close to the muscle to minimize the dead space before the blood entered the muscle. This was important so that the switch to deoxygenated blood would result in a rapid reduction in O2 delivery even at normal muscle blood flow. At the muscle blood flows used in the present study, it was calculated that the muscle was perfused with the deoxygenated blood within 3-4 s of the switch.
Before the contraction period, the resting muscle was stretched until the contractile response was greatest. Isometric, tetanic muscle contractions were elicited by stimulation of the sciatic nerve with trains of stimuli (6-8 V of 0.2-ms duration at 50 Hz) lasting 0.2 s at a rate of one contraction every 2 s (~60-70% of the muscle maximal oxygen uptake). These submaximal contractions were chosen because prior studies (15, 18) indicated that tetanic contractions at this rate can continue for extended periods of time with little fatigue if O2 delivery is normal, yet when O2 delivery is diminished, the force production is immediately affected. Each experiment (n = 5) consisted of an 8-min contraction period. The first 3 min of contractions were with perfusion by the dog's blood (normal PO2) at a pressure of 140 mmHg, which allowed the muscle to reach a steady state of blood flow and force development with no fatigue (control treatment). At the end of the initial 3-min control period, a 2-min period of complete ischemia was imposed on the contracting muscle by reducing blood flow to zero (perfusion pump turned off and venous catheter clamped). After the ischemic episode, the contracting muscle was then quickly reperfused (at the steady-state blood flow previously measured in the initial 3-min control period) for 30 s with the deoxygenated blood, for 30 s with normal oxygenated blood, and back again for 30 s with the deoxygenated blood. After these treatments, the contracting muscle was perfused at the control blood flow with normal oxygenated blood until 8 min, at which time stimulation was halted. Changes in developed force were measured during each treatment period. This was defined as the difference in force development (N/100 g mass) from the start to the conclusion of a particular treatment.Measurements. Arterial blood samples were obtained from the arterial line entering the muscle. These samples were drawn anaerobically during each of the two conditions of oxygenation (normal and deoxygenated) and were kept on ice. Blood PO2, PCO2, and pH were measured within 5-8 min with a blood-gas analyzer (IL model 813) at 37°C, whereas hemoglobin concentration, percent O2 saturation, and percent CO saturation were measured with an IL 282 CO-oximeter. These instruments were calibrated before each experiment. The muscle was removed and weighed at the end of each experiment.
Statistics. Repeated-measures analysis of variance, at the 0.05 level of significance, was used to determine any differences between the means of each group.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Mean weight of the exercised gastrocnemius muscles (n = 5) was 72 ± 4 (SE) g.
During the 3-min control period, the muscle achieved a steady state of
contractile force (maximal force development was 470 ± 40 N/100 g),
and muscle blood flow (70 ± 8 ml · 100 g
1 · min1) and
perfusion pressure (138 ± 4 mmHg) were steady. There was no
significant fall in force development during this control period (end
force = 460 ± 40 N/100 g; see Fig. 1).
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At the initiation of the 2 min of complete ischemia, force began to fall immediately, and by the end of this zero blood flow condition, force had fallen to 39 ± 6% (P < 0.01) of the preischemic value (end force = 170 ± 20 N/100 g; see Fig. 1).
Table 1 presents the principal variables of
O2 transport and acid-base balance in the blood perfusing
the muscles during the oxygenated and deoxygenated conditions that were
imposed on the contracting muscle after the 2-min ischemic period. The
only variable listed in Table 1 that was significantly different
between the oxygenated vs. deoxygenated conditions was the
PO2.
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Figure 1 illustrates the mean response of developed force from the
start of the repetitive contractions until recovery. On the
reintroduction of the control blood flow value (66 ± 10 ml · 100 g1 · min1), but
with deoxygenated blood, mean muscle force development continued to
fall (P < 0.01) to 140 ± 20 N/100 g during this 30-s period
(see Fig. 1). Only when the oxygenated blood was restored for 30 s did
mean muscle force development recover, with an immediate and rapid
restoration of tension to 310 ± 30 N/100 g, a 221 ± 43% increase
(P < 0.01). When the muscle was then perfused (blood flow
held constant) for the second time with deoxygenated blood, mean muscle
force development fell again, to 180 ± 30 N/100 g (P < 0.01). Muscle force recovered continually (up to 350 ± 30 N/100 g) on the final restoration of normal blood flow and
oxygenation up to the 8-min stopping point.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of this study demonstrated that force generation in contracting skeletal muscle began to rapidly recover with reperfusion after a short period of total blood flow occlusion and that this only occurred if the restoration of blood flow was with oxygenated blood. These results are consistent with the hypothesis that it is the reintroduction of O2 to postischemic muscle, rather than an alternative factor related to blood flow, that is important for the recovery of force production during reperfusion after a 2-min period of total ischemia.
Effects of ischemia on muscle force production. Repeated contractions at a relatively high frequency result in a loss of tension development (fatigue), followed by a prolonged period in which the maximal force generation remains impaired. It has been suggested (26) that, during high-frequency contractions, fatigue will occur when ATP generation from oxidative and substrate-level phosphorylation cannot support the demand of the ATPases. The factors that result in the reduction of force development with repetitive contractions have been extensively studied (see Refs. 9, 28, 30) and include metabolic disturbances (changes in Pi, ADP, and H+) that may inhibit both the contractile and Ca2+ release sites (7, 22, 25, 27, 29), with little disruption of intracellular ATP levels (4, 14, 17, 25).
Reductions in blood flow (ischemia) to either working skeletal (18, 24) or cardiac muscle (1, 21) result in a fall in force production that can occur within seconds of the ischemic initiation. When the ischemia is sudden and severe (as in the present study), whether the reduction in force development may be due to similar mechanisms as occur during "high-frequency" fatigue is unclear (1, 20). However, if the blood flow reduction is only partial, contracting muscle has the capacity to reduce force development to the level at which the new steady-state force production matches that rate of respiration attainable from the limited amount of O2 available (3, 10, 11, 15). In this way, skeletal muscle can "downregulate" force production to match O2 availability with minimal activation of substrate-level phosphorylation and thereby minimize intracellular disruption of homeostasis (16, 20). Although respiration and force production can be dramatically reduced under these conditions, there may only be minor changes in the intracellular concentrations of ATP, phosphocreatine, and lactate (16, 20). This strategy maintains the "tight coupling" (13) of force production to mitochondrial respiration so that the O2 cost of contractions remains constant. The manner by which muscle can minimize intracellular metabolic disruption, by downregulating ATPase activity to match the rate of oxidative phosphorylation, during conditions of partial ischemia is not well understood. In the present study, the complete elimination of blood flow certainly resulted in intracellular metabolic disruption (because of the rapid reduction in oxidative phosphorylation) that contributed to the fall in force. However, because the total ischemia was only for 2 min, force continued to fall during the entire ischemic period, and a new steady state of force development was not attained. However, because the total ischemic period was brief, the metabolic instability that developed during the 2-min period was not yet severe enough to completely abolish tension development and induce cellular damage, as can occur if the ischemia is for a long duration.Recovery of muscle force production after ischemia. Restoration of force subsequent to a fatiguing bout of contractions will depend on the degree of metabolic disturbance that occurred and the time allowed for recovery. However, even when the metabolic disturbances are corrected during the recovery period, there can remain substantial contractile dysfunction (2, 23, 27), and it has been recently suggested (6) that the sustained impairment may be related to prolonged elevated intracellular Ca2+. In addition, recovery of muscle function after fatiguing contractions in whole muscle may depend in part on keeping blood flow elevated and washing out metabolic waste products. For example, a "warm-down" period, in which blood flow remains elevated after high-intensity exercise, has been shown to improve subsequent muscle performance (5). We have previously shown (18) that whole muscle contractility is affected within seconds on initiation of ischemia and that this process is dependent on O2 availability and not some other factor related to the cessation of blood flow. However, the time course involved with recovery of force production on restoration of normal perfusion after a period of ischemia, and whether this process may be related to O2 availability or the washout of various metabolites that may inhibit contractility, is unknown.
The results of the present study demonstrated that force generation began to recover rapidly after the brief bout of total ischemia, but only with oxygenated reperfusion. Muscle blood flow perfusion at control levels, but with deoxygenated blood, only led to further declines in force generation (see Fig. 1). However, within 2-3 s of reperfusion with oxygenated blood, force began to climb dramatically and recovered to 67% of normal within 30 s (see Fig. 1). The rapid recovery on reperfusion with oxygenated blood suggests that the "downregulation" of force production during ischemia may involve somewhat different pathways from those involved during "high-frequency fatigue," because the recovery of force production after the ischemic inhibition was rapidly alleviated by restoration of oxygenation. If inhibition of Ca2+ release is involved in the fall in force generation during ischemia as in normal fatigue processes (see Refs. 9, 28, 30), it is unclear by what mechanism O2 rapidly alleviated this inhibition, especially considering that intracellular levels of ATP are not significantly affected during this downregulation of force (17) in oxidative skeletal muscle. This seems to indicate that the relationship between O2 availability and contractile function is tightly matched in submaximally working muscle in steady-state conditions. However, the manner in which ATP utilization at the contractile sites is so rapidly coupled to ATP production by the cellular respiratory system during reperfusion is uncertain. The instantaneous changes in O2 delivery induced in the present study would rapidly alter the pressure head for O2 diffusion from the capillary to the mitochondria, likely resulting in a fall in intracellular PO2 during the deoxygenated perfusion condition and an increase in PO2 during the oxygenated one. The corresponding alterations in mitochondrial PO2 may result in changes in the concentrations of the other substrates of oxidative phosphorylation (14, 17, 31). This might be important in the immediate contractile response to ischemia and reoxygenation if the intracellular Pi concentration is immediately reduced (by phosphocreatine restoration), as Pi has been shown to directly affect contractile function (8, 25, 29). It seems unlikely that rapid alterations in the intracellular H+ concentration, which have been shown to diminish contractility (7, 8, 22), would be as immediate as the contractile response in the present study to deoxygenation and reoxygenation. Reperfusion of the contracting muscle with deoxygenated blood resulted in a continued fall in force generation (see Fig. 1), suggesting that under these conditions the washout of metabolites (primarily lactic acid) that are known to inhibit contractility was not adequate to augment tetanic force. However, it is likely that the washout of metabolites, or slow return of intracellular regulators of tetanic force generation (for example Pi and ADP) to control levels, played some role in the whole muscle response seen in the present study, as force generation continued to slowly recover over the time period of the final reoxygenation treatment (see Fig. 1). Using the whole muscle model in this present study, we could not determine whether this steady increase in force was a result of heterogeneous reoxygenation of some fibers (possibly due to blood flow heterogeneity), the slow washout of contractile inhibitors, or slow recovery of intracellular metabolites that may inhibit tension development. Finally, it should be noted that muscle blood flow after the ischemic period was adjusted immediately to preischemic values, thereby eliminating any potential hyperemic response. However, this does not alter the interpretation of the muscle force-generation response to the blood flow restoration, with or without O2.Conclusion. These findings demonstrated that skeletal muscle force can rapidly recover during reperfusion after a brief period of total ischemia, and that this recovery is dependent on O2 availability and not an alternative factor related to blood flow per se.
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ACKNOWLEDGEMENTS |
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This research was supported by National Institutes of Health Grants HL-17731 and AR-40155.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. C. Hogan, Dept. of Medicine 0623-A, Univ. of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0623 (E-mail: mchogan{at}ucsd.edu).
Received 12 February 1999; accepted in final form 19 August 1999.
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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