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(Chest. 2003;123:875-881.)
© 2003 American College of Chest Physicians

Effects of Chronic Intermittent Asphyxia on Rat Diaphragm and Limb Muscle Contractility*

Michelle McGuire, PhD; Mary MacDermott, PhD and Aidan Bradford, PhD

* From the Department of Physiology, Royal College of Surgeons in Ireland, Dublin, Ireland.

Correspondence to: Aidan Bradford, PhD, Department of Physiology, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland; e-mail: abradfor{at}rcsi.ie


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: In obstructive sleep apnea (OSA), there is intermittent upper airway (UA) collapse due to an imbalance between the collapsing force generated by the diaphragm and the stabilizing force of the UA muscles. This results in chronic intermittent asphyxia (CIA). We have previously shown that CIA affects UA muscle fatigue, but little is known about the effects of chronic hypoxia on diaphragm or on limb muscle contractile properties and structure.

Design: Rats were exposed to asphyxia and normoxia twice per minute for 8 h/d for 5 weeks to simulate the intermittent asphyxia of OSA in humans. Isometric contractile properties were determined from strips of isolated diaphragm, extensor digitorum longus (EDL), and soleus muscles in Krebs solution at 30°C. EDL and soleus type 1 (slow, fatigue resistant), type 2A (fast, fatigue resistant), and type 2B (fast, fatigable) fiber distribution was determined using adenosine triphosphatase staining.

Results: CIA caused a significant increase in diaphragm, EDL, and soleus fatigue, and reduced recovery from fatigue. Most of the other contractile properties were unaffected aside from a small reduction in diaphragm half-relaxation time and EDL twitch tension and a small shift to the left in the EDL force-frequency curve. There was no change in soleus fiber-type distribution and a small increase in EDL type 2A fibers (46.1 ± 1.2% vs 49.9 ± 1.4%, control vs CIA [mean ± SD]).

Conclusions: CIA increases diaphragm, EDL, and soleus muscle fatigue. We speculate that if this also occurs in OSA, it would contribute to the pathophysiology of the condition.

Key Words: diaphragm • extensor digitorum longus • intermittent asphyxia • soleus


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Sleep-disordered breathing is a common condition1 characterized by hypopnea and apnea that are caused by either a decrease in ventilatory drive, termed central apnea, or more commonly by obstruction of the upper airway (UA), termed obstructive sleep apnea (OSA).2 3 The hypopnea and apnea cause intermittent hypoxia and hypercapnia.4 5 We have shown previously that chronic intermittent asphyxia (CIA) affects rat UA muscle contractile properties. CIA has no effect on UA muscle twitch or tetanic tension but causes an increase in geniohyoid muscle fatigue.6 7 A similar effect in humans could lead to a vicious cycle of further asphyxia and further UA muscle fatigue. During inspiration, the contraction of the diaphragm also plays an important role in determining UA patency because maintaining patency is a balance between the dilating and stabilizing forces produced by the UA muscles and the subatmospheric, collapsing pressures generated by the diaphragm.8 However, the effects of CIA on diaphragm function are unknown. Therefore, the present study was undertaken to examine the effects of CIA on diaphragm contractile properties.

It is known that there are structural abnormalities in the UA muscles but not in the limb muscles of the English bulldog, which is an animal model of human OSA.9 Since the UA muscles encounter increased activity and load in these animals, whereas the limb muscles would not be expected to encounter similar effects, it was proposed that the cause of the changes in UA muscle structure was the altered UA muscle activation.9 However, we have previously proposed an alternative hypothesis, ie, that CIA causes changes in UA muscle function.7 Therefore, we also wished to examine the effects CIA on limb muscle structure and function in order to see if any effects observed were generalized or if they were specific to respiratory muscles.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Male Wistar rats were randomly assigned to a control and CIA groups and placed in restrainers with their heads surrounded by hoods. All the procedures used were in accordance with the Cruelty to Animals Act, 1876 and European Union Directive 86/609/EC. In the CIA group (n = 16), room air was delivered to the hoods for 15 s followed by infusion of 100% nitrogen for 15 s. We have shown previously that this results in nadir PaO2 values of 55 to 65 mm Hg.10 A nadir PaO2 of 54.7 mm Hg has been reported in a group of 20 patients with OSA.11 This cycle was repeated for 8 h/d for 5 d/wk for 5 weeks. The control group (n = 16) received air that was switched to air from a separate source every 15 s using identical solenoid valves using the same flow rates as used for the CIA group. This cycle was repeated for 8 h/d for 5 d/wk for 5 weeks.

At the end of the 5-week treatment period, animals were anesthetized with pentobarbitone sodium (60 mg/kg intraperitoneally), tracheostomized, and placed on mechanical ventilation with room air. Body temperature was maintained at 37°C using a thermostatically controlled heating blanket and radiant heat. A femoral artery and vein were cannulated to record arterial BP and to administer supplementary anesthetic, respectively. An incision was made in the skin of the lower part of the hind limb to expose the tibialis anterior muscle. The distal tendon of this muscle was cut and the muscle reflected to expose the extensor digitorum longus (EDL), which was carefully removed. The tendons of the gastrocnemius and plantaris were cut and the muscles deflected to expose the soleus, which was also carefully removed. A transverse incision was made immediately posterior to the rib cage, and the thorax was opened by a transverse incision just above the diaphragm. A strip of costal diaphragm was removed with the rib margin and central tendon left intact.

The muscles were removed rapidly and prepared for either adenosine triphosphatase (ATPase) staining or for contractile studies but never for both. Longitudinal strips of approximately 2 mm in diameter were suspended vertically in warmed (30°C), oxygenated (95% oxygen/5% carbon dioxide) Krebs solution (pH 7.4) containing the following: NaCl, 120 mmol; KCl, 5 mmol; Ca gluconate, 2.5 mmol; MgSO4, 1.2 mmol; NaH2PO4, 1.2 mmol; NaHCO3, 25 mmol; and glucose, 11.5 mmol. One end of the muscle was fixed and the other end attached to an isometric force transducer mounted on a micropositioner. The muscles were stimulated with platinum electrodes (supramaximal voltage, 1-ms duration), and contractions were recorded using an analog/digital converter and microcomputer. Isometric twitch tension, tetanic tension, twitch/tetanic tension ratio, contraction time, half-relaxation time, the force-frequency relationship, fatigue, and recovery from fatigue, were measured. These properties determine the behavior of these muscles in vivo. Thus, the twitch and tetanic tension determine the ability of the muscles to generate force, the force-frequency relationship determines the ability to generate force at different levels of activation, and fatigue determines the degree of loss of force-generating ability with prolonged activation.

Protocol
Following placement in the Krebs solution and attachment to a force transducer, a period of 30 min was allowed for equilibration. Optimal length was determined, and the muscle was held for the remainder of the experiment at this length. The muscle was then stimulated for 300 ms at each of the following frequencies: 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 Hz. An interval of 2 min was allowed between each stimulus. Ten minutes following this force-frequency relationship determination, fatigue was induced by stimulation with 30 Hz trains of 300-ms duration, with the frequency of the trains set at 0.5 Hz for a total of 5 min. Recovery from fatigue was determined by measuring twitch tension every 5 min for 30 min after the end of the fatigue protocol. Studying fatigue in this way has certain limitations. It does not take into account changes in blood flow, systemic changes, alterations in pattern and frequency of activation, and neuromuscular excitability, etc. The protocol was chosen to mimic, to some extent, the normal pattern of muscle excitation. Phrenic activation of the diaphragm during quiet breathing has a rate of approximately 30 Hz, but this can rise to approximately 60 Hz with increased inspiratory resistance.12 The duration of activation used in the present experiments of 300 ms approximates the inspiratory time of rats,13 although the frequency of the trains used was less than that for the normal respiratory frequency for rats.13

ATPase Staining
In order to distinguish between type 1 and type 2 fibers and to further subdivide the type 2 fibers into 2A and 2B, ATPase in incubating solutions of pH 4.2, pH 4.6, and pH 9.4 was used. Excess blood and tissue fluid was removed from the muscles, and a piece from the center of the muscle of approximately 5 x 5 mm was used. The muscle was placed in talcum powder, dusted off, and placed in liquid N2 (- 180°C) for 1 min. The muscle was then transferred to a cryogenic vial for storage at - 70°C. Frozen sections of 12-µm thickness were prepared using a cryostat and air-dried for 5 h. Sections were preincubated at 4°C in 0.1 mol/L sodium acetate/acetic acid buffer at either pH 4.2 (36.8 mL of 0.1 mol/L acetic acid, 13.2 mL of 0.1 mol/L sodium acetate, and 50 mL H2O, pH to 4.2 using 0.1 mol/L HCl) or pH 4.6 (25.5 mL of 0.1 mol/L acetic acid, 24.5 mL of 0.1 mol/L sodium acetate, and 50 mL H2O, pH to 4.6 using either 0.1 mol/L HCL or 0.1 mol/L NaOH) for 10 min. For pH 9.4 incubation, sections were incubated in 0.1 mol/L glycine buffer with 0.75 mol/L CaCl2 and adenosine triphosphate (1 mg of adenosine triphosphate to 2 mL of glycine/CaCl2 solution, pH to 9.4 using 0.1 mol/L NaOH) at 37°C for 45 min. The rest of the staining procedure was the same for all three pH values. The sections were rinsed well in distilled water and then immersed in a 2% cobalt chloride solution for 5 min. Following this, the sections were rinsed in three changes of distilled water and immersed in a dilute (1:10) ammonium sulfate solution for 30 s. The slides were rinsed in running tap water for 5 min. Sections incubated at pH 4.2 were lightly stained in Harris hematoxylin. All sections were then dehydrated in 95%, 99%, and 99% alcohol and cleared in xylene. Due to technical difficulties, we were unable to complete these procedures successfully for the diaphragm.

Data Analysis
Specific tension was calculated in Newtons per square centimeter of strip cross-sectional area. Cross-sectional area was calculated by weighing the muscle strip after removal from the bath and blotting dry and dividing this by the product of the optimal length and muscle density, assumed to be 1.06 mg/mm3. For the force-frequency curves, values were expressed at each frequency as a percentage of the maximal value. Fatigue was analyzed by expressing the force generated by the first pulse of the stimulus train at 1, 2, 3, 4, and 5 min as a percentage of the value of the first pulse of the first train. Recovery from fatigue was determined by expressing the ratio (recovery tension -fatigue tension/initial tension - fatigue tension) as a percentage where recovery tension is the twitch tension measured during recovery, fatigue tension is the twitch tension measured immediately after the 5-min fatigue protocol, and initial tension is the twitch tension measured immediately before the fatigue protocol. These values, the absolute values for specific twitch and tetanic tension, the twitch/tetanic tension ratio, and the contraction and half-relaxation times were expressed as means ± SD. Fiber types were determined by the different pHs in which the sections were incubated.9 The different fiber types were counted and expressed as a percentage ± SD of the total number of fibers. These values and contractile values were used to compare statistically the control and CIA groups using analysis of variance and the Fisher least significant difference test, with p < 0.05 taken as significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
CIA caused an increase in fatigue and a decrease in recovery from fatigue in all three muscles (Figs 1 2 3 ). Generally, CIA had little effect on the other contractile properties (Table 1 ), except for a small decrease in diaphragm half-relaxation time (Table 1) , a small decrease in EDL twitch tension (Table 1) , and a small shift to the left of the EDL force-frequency curve (Fig 4 ).



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  		Figure 1. Effect of CIA on diaphragm fatigue. Graphs show fatigue (top) and recovery from fatigue (bottom). Lines indicate values expressed as means ± SD for control (-{square}-, n = 16) and CIA (-{blacksquare}-, n = 16). *Indicates significant difference (p < 0.05) between control and CIA.

 


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  		Figure 2. Effect of CIA on EDL fatigue. Graphs show fatigue (top) and recovery from fatigue (bottom). Lines indicate values expressed as means ± SD for control (-{square}-, n = 8) and CIA (-{blacksquare}-, n = 8). *Indicates significant difference (p < 0.05) between control and CIA.

 


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  		Figure 3. Effect of CIA on soleus fatigue. Graphs show fatigue (top) and recovery from fatigue (bottom). Lines indicate values expressed as means ± SD for control (-{square}-, n = 8) and CIA (-{blacksquare}-, n = 8). *Indicates significant difference (p < 0.05) between control and CIA.

 

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  		Table 1. Effect of CIA on Muscle Contractile Properties*

 


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  		Figure 4. Effect of CIA on the force-frequency curve for EDL muscle. Lines indicate values expressed as means ± SD for control (-{square}-, n = 8) and CIA (-{blacksquare}-, n = 8). *Indicates significant difference (p < 0.05) between control and CIA.

 
The fiber type distribution (determined using ATPase staining) of the EDL and soleus in control and CIA-treated animals is shown in Figure 5 . CIA had no effect on EDL type 1 or type 2B fibers but slightly increased the number of type 2A fibers (46.1 ± 1.2% vs 49.9 ± 1.4%, control vs CIA). CIA had no effect on soleus fiber type.



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  		Figure 5. EDL (left) and soleus (right) fiber-type distribution in CIA (-{square}-, n = 8) and control (-{blacksquare}-, n = 8) rats.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These results show that CIA causes an increase in diaphragm, EDL, and soleus muscle fatigue. CIA had little or no effect on the other contractile properties of all three muscles and little effect on fiber-type distribution. We measured fiber-type distribution in an attempt to understand the cause of the functional changes observed. Type 1 fibers have slow contractile kinetics and are fatigue resistant, whereas type 2B fibers are fast and are highly fatigable. The 2A fibers are fast and fatigue resistant. Thus, for example, a transformation from type 1 to type 2B fibers would be expected to result in an increase in fatigability. The three muscles studied in the present experiments have different fiber-type distributions. The soleus was chosen because it has a very high number of type 1 fibers, whereas the EDL was chosen because it has a large number of type 2B fibers.14 The diaphragm has an approximately equal distribution of all three fiber types.15 The relevance of studying rat muscle in relation to human OSA stems from the similarities, compared to humans, of rat muscle responses to overload stress, resistance training, space flight, and hind limb suspension, as described by Baldwin and Haddad.16

In the present experiments, there was a small increase in type 2A fibers and no effect on type 1 or 2B fibers in the EDL, and similar effects have also been observed in response to chronic continuous hypoxia.17 However, in the latter study, there was also an increase in type 2A fibers in the soleus, whereas there was no change in fiber composition of the soleus in the present experiments. This lack of effect on soleus fiber type is consistent with other studies using chronic continuous hypoxia in which there was no effect on soleus muscle structure in rats18 19 20 or guinea pigs.21

We have shown previously that CIA alters UA muscle fiber type.7 Geniohyoid muscle type 1 fibers were reduced and type 2B fibers were increased, whereas sternohyoid type 1 and 2A fibers were increased and type 2B fibers were decreased. Unfortunately, we were unable to determine diaphragm fiber-type distribution in the present experiments. Presumably, we would have seen a different pattern of effects since the effects of blood gas changes appear to depend on the initial fiber-type distribution of the muscle. It would have been useful to see if there was a correlation between changes in diaphragm fiber type and the observed changes in diaphragm contractile properties.

Very little is known about the effects of chronic hypoxia on skeletal muscle contractile properties or on diaphragm structure or function.22 . Chronic hypoxia has been shown by Itoh et al14 to reduce force and to shift the force-frequency relationship to the left in rat EDL but to have no effect on force or the force-frequency relationship of the soleus. This is consistent with the findings in the present experiments using intermittent asphyxia except that in the Itoh et al study, EDL fatigue was reduced and soleus fatigue was unaffected. For the diaphragm, Clanton et al23 reported that 10 days of intermittent hypoxia in rats increased force, shifted the force-frequency curve to the left, and had no effect on fatigue. In our study, diaphragm force and the force-frequency curve were unaffected and fatigue was increased by 5 weeks of intermittent asphyxia. These differences may be due to the use of hypoxic hypocapnia in the study by Clanton et al23 compared to hypoxic hypercapnia in the present study and to the very different durations of hypoxia/asphyxia exposure, ie, 10 days in the study by Clanton et al23 and 5 weeks in the present experiments. Overall, in the present experiments, the increase in fatigue observed in all three muscles, and the minor effects on other contractile properties agree with our previous findings for CIA on UA muscles.7 Thus, the geniohyoid and sternohyoid twitch and tetanic tension, twitch/tetanic tension ratio, and force-frequency relationship were unaffected and geniohyoid fatigue was increased, although sternohyoid fatigue was reduced.7 Generally, chronic continuous hypoxia has been reported to have little effect on force and fatigue in humans,24 25 26 although forearm muscle force and endurance was found to be reduced by 32 days of high-altitude exposure.27

We did not observe any effect of CIA on soleus fiber-type distribution and only a small increase in EDL type 2A fibers. Therefore, the effects of CIA on contractile properties that we observed must be largely due to changes in excitation-contraction coupling. It is known that fatigue can arise due to a decline in calcium release from the sarcoplasmic reticulum28 resulting from H+ accumulation in the sarcoplasm.29 It is also known that acute hypoxia causes a decrease in muscle pH and promotes fatigue.29 Fatigue is also associated with an increase in reactive oxygen species,30 and chronic continuous hypoxia is known to increase antioxidant enzyme concentrations, indicative of excess oxygen-derived free radical production.31

In conclusion, the main finding of the present investigation is that CIA increases fatigue in the diaphragm and in limb muscles. If similar changes occur in humans, then the increase in diaphragm fatigability would tend to reduce the collapsing force during apneas. We have suggested previously that the increase in UA muscle fatigue caused by CIA would exacerbate OSA,7 but the present finding of increased diaphragm fatigue would offset this effect. Little is known about the role of diaphragm fatigue in OSA. In one study, diaphragm fatigue did not occur during the course of the night in OSA.32 However, in this study, the number of patients was small, and there are technical difficulties in assessing in situ diaphragm fatigue in humans. Since fatigue was increased by CIA in the diaphragm, EDL, and soleus, and since CIA also increases fatigue in UA muscle,7 we speculate that this is a generalized effect of blood gas changes on skeletal muscle. We further speculate that this may contribute to the subjective sensation of fatigue experienced by patients with OSA but which is generally believed to be due to increased cytokine concentrations or interruption of sleep.33


   Acknowledgements
 
The authors thank T. Dowling and J. Slattery for technical assistance.


   Footnotes
 
Abbreviations: ATPase = adenosine triphosphatase; CIA = chronic intermittent asphyxia; EDL = extensor digitorum longus; OSA = obstructive sleep apnea; UA = upper airway

This work was supported by the Royal College of Surgeons in Ireland.

Received for publication March 7, 2002. Accepted for publication September 11, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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