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(Chest. 2002;122:1012-1017.)
© 2002 American College of Chest Physicians

Effects of Chronic Episodic Hypoxia on Rat Upper Airway Muscle Contractile Properties and Fiber-Type Distribution*

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

* From the Department of Physiology, Royal College of Surgeons in Ireland, St. Stephen’s Green, 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: Contraction of upper airway (UA) muscles such as the geniohyoids and sternohyoids dilates and/or stabilizes the UA, thereby maintaining its patency. Obstructive sleep apnea (OSA) is caused by episodes of UA collapse, and this results in chronic episodic hypoxia. Chronic continuous hypoxia affects skeletal muscle structure and function, but the effects of chronic episodic hypoxia on UA muscle structure and function are unknown.

Design: Rats were exposed to alternating periods of hypoxia and normoxia twice per minute for 8 h/d for 5 weeks in order to mimic the intermittent hypoxia of OSA in humans. Isometric contractile properties were determined using strips of isolated geniohyoid and sternohyoid muscles in physiologic saline solution at 30°C. Fiber-type distribution was determined using adenosine triphosphatase staining.

Results: Chronic episodic hypoxia had no significant effect on twitch or tetanic tension, twitch/tetanic tension ratio, contractile kinetics, tension-frequency relationship, or fiber-type distribution for either the sternohyoid or geniohyoid muscle. However, chronic episodic hypoxia did significantly increase sternohyoid and geniohyoid fatigue and reduced recovery from fatigue.

Conclusions: Chronic episodic hypoxia increases UA muscle fatigue, an effect that may compromise the maintenance of UA patency.

Key Words: episodic hypoxia • geniohyoid • sternohyoid


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Upper airway (UA) muscles such as the geniohyoid and sternohyoid muscles play a crucial role in maintaining the patency of the UA.1 In obstructive sleep apnea (OSA), UA patency is compromised so that there is episodic apnea during sleep due to the collapse of the UA during inspiration.2 Normally, contraction of UA muscles opposes this collapse by stabilizing and dilating the airway.1 2 3

The pathophysiology of OSA is poorly understood, but there is abundant evidence that the actions of the UA muscles are pivotal in determining pharyngeal stability. A variety of UA reflexes have been described that regulate UA patency by controlling UA muscle activity,4 5 6 7 and there is evidence that abolition of these reflexes causes UA collapse in animals8 and humans,9 and that this reflex function is abnormal in patients with OSA.10 There is also evidence implicating intrinsic UA muscle function in the pathophysiology of OSA. Thus, UA muscle structure is abnormal in the English bulldog, an animal model of OSA,11 and in humans with OSA,12 13 although it is not clear if these structural abnormalities are translated into changes in UA muscle contractile function. Nor is it clear if these effects are a cause or an effect of the condition. It has been hypothesized that the chronically enhanced UA muscle activity observed in patients with OSA patients compared to normal individuals, and the repetitive bouts of greatly increased UA muscle activity that terminate the apneic events cause the abnormalities of UA muscle function.14 This has been ascribed to the increased forces generated by this increased activity.14 The usual change in UA muscle structure that has been described has been an increase in fast-twitch muscle fibers.11 12 13 15 Since chronic continuous hypoxia can cause an increase in fast fibers,16 we questioned whether the hypoxia of OSA might contribute to changes in UA muscle structure and function. In OSA, the multiple episodes of UA collapse are accompanied by episodes of systemic hypoxia rather than continuous hypoxia, but the effects of chronic episodic hypoxia on skeletal muscle are unknown. The present investigation tests the hypothesis that chronic episodic hypoxia affects UA muscle structure and function by determining the fiber-type distribution and the in vitro contractile properties of geniohyoid and sternohyoid muscles in rats exposed to episodic hypoxia for 5 weeks.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Procedures were carried out in accordance with the Cruelty to Animals Act, 1876, and European Union Directive 86/609/EC. Wistar rats were randomly assigned to two groups of 16 rats each. The animals were placed in restrainers with their heads surrounded by hoods. In one group (the hypoxic group), the percentage of inspired oxygen was controlled by delivering a flow of air to the hoods for 15 s followed by 100% nitrogen for 15 s. We have shown previously that this results in nadir arterial blood PO2 values of 55 to 65 mm Hg.17 Flow was switched between air and nitrogen using timed solenoid valves. This cycle was repeated for 8 h/d for 5 d/wk for 5 weeks. The minimum percentage of inspired oxygen in the hoods was measured three times daily (at approximately 0 h, 4 h, and 8 h) in eight rats of the hypoxic group, and mean daily minimum values were calculated (Fig 1 ). The other group (the control group) received air that was switched to air from a separate source every 15 s using identical solenoid valves with the same flow rates as for the hypoxic group. This cycle was repeated for 8 h/d for 5 d/wk for 5 weeks.



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  		Figure 1. Daily minimum inspired concentration of oxygen (percentage of inspired oxygen) measured three times per day in eight animals. Values are means ± SD.

 
After the 5-week treatment period, animals were anesthetized (pentobarbitone sodium, 60 mg/kg intraperitoneal), tracheostomized, and placed on mechanical ventilation. A femoral artery and vein were cannulated with the aid of a microscope in order to record arterial BP and to administer supplementary anesthetic, respectively. Core temperature was maintained at 37°C using a thermostatically controlled heating blanket and radiant heat. The digastric muscles were separated to reveal the omohyoid muscle, which was cut to expose the underlying geniohyoid muscles that run as two parallel strips from the midpoint of the mandible to the hyoid bone. The sternohyoid muscles running from the sternum to the hyoid bone were also exposed. The muscles were removed rapidly and prepared for adenosine triphosphatase (ATPase) staining or for contractile studies using longitudinal strips of 1 to 2 mm in diameter that were suspended vertically in a water-jacketed bath in warmed (30°C), oxygenated (95% oxygen, 5% carbon dioxide) physiologic saline 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; and glucose, 11.5 mmol. One end of the muscle strip was fixed, and the other end was attached to an isometric force transducer mounted on a micropositioner. Isometric twitch tension, tetanic tension, twitch/tetanic tension ratio, contraction time, half-relaxation time, the tension-frequency relationship, fatigue, and recovery from fatigue were measured using field stimulation (supramaximal voltage, 1 ms in duration) with platinum electrodes and recorded using an analog-to-digital converter and microcomputer.

Protocol
After an equilibration period in the bath of 30 min, muscle length was varied using the micropositioner and the optimal length was determined, ie, the length producing maximal twitch tension. The muscle was held for the remainder of the experiment at this length. The muscle was then stimulated at 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 Hz for 300 ms at each frequency and allowing 2 min between each stimulus. Ten minutes following this tension-frequency determination, fatigue was induced by stimulation at 30 Hz with 300 ms trains of 0.5 Hz for 5 min. Recovery from fatigue was determined by measuring twitch tension every 5 min for 30 min after the end of the fatigue protocol.

ATPase Staining
ATPase in incubating solutions of pH 4.2, pH 4.6, and pH 9.4 was used in combination to distinguish between type 1 and type 2 fibers and to further subdivide the type 2 fibers into 2A and 2B. Excess blood and tissue fluid was removed using blotting paper. A section from the center of the muscle of approximately 5 x 5 mm was used. The muscle was placed in talcum powder and the excess was dusted off before being placed into liquid N2 (- 180°C) for 1 min. The muscle was then placed into a cryogenic vial and stored at - 70°C. Frozen sections of 12 µm in thickness were prepared using a cryostat and allowed to air-dry 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. The sections were then rinsed well in three changes of distilled water and then immersed in a dilute (1:10) ammonium sulfate solution for 30 s. The slides were rinsed well 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.

Data Analysis
Specific tension was calculated in newtons per square centimeter of strip cross-sectional area. Cross-sectional area was approximated 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 tension-frequency relationship, values were normalized by expressing them at different frequencies as a percentage of the maximal tetanic value. For the fatigue protocol, values were normalized 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 ratio, and the contraction and half-relaxation times were expressed as means ± SD. Different fiber types were determined by the different pHs in which the sections were incubated.18 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 hypoxic groups using analysis of variance and the Fisher least significant difference test, with p < 0.05 taken as significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
There was no significant difference in the body mass between the control and hypoxic groups at the beginning or end of the 5-week treatment period (Fig 2 ). Compared to the geniohyoid muscle, the sternohyoid muscle showed greater force production, faster contractile kinetics, and less endurance (Table 1 ; Figs 3 , 4 ).



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  		Figure 2. Body weight in control rats (n = 16) and rats with chronic intermittent hypoxia (n = 16) during the 5-week treatment period. Values are means ± SD.

 

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  		Table 1. Effect of Chronic Episodic Hypoxia on Geniohyoid and Sternohyoid Contractile Properties*

 


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  		Figure 3. Effect of chronic intermittent hypoxia on sternohyoid muscle contractile properties. Graphs show the tension-frequency relationship (top), fatigue (middle), and recovery from fatigue (bottom). Lines indicate values expressed as means ± SD for control rats ({square}, n = 16) and rats with chronic intermittent hypoxia ({blacksquare}, n = 16). *Significant difference between control and chronic intermittent hypoxia.

 


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  		Figure 4. Effect of chronic intermittent hypoxia on geniohyoid muscle contractile properties. Graphs show the tension-frequency relationship (top), fatigue (middle), and recovery from fatigue (bottom). Lines indicate values expressed as means ± SD for control ({square}, n = 16) and chronic intermittent hypoxia ({blacksquare}, n = 16). *Significant difference between control and chronic intermittent hypoxia.

 
For both the sternohyoid and geniohyoid muscles, chronic intermittent hypoxia had no significant effect on twitch or tetanic tension, twitch/tetanic tension ratio, contractile kinetics (Table 1) , or tension-frequency relationship (Figs 3 , 4) . However, chronic episodic hypoxia significantly increased sternohyoid and geniohyoid fatigue and reduced recovery from fatigue (Figs 3 , 4) .

The fiber-type distribution of both the sternohyoid and geniohyoid in control and chronic episodic hypoxia-treated animals is shown in Figure 5 . Control geniohyoid muscle contained 12% type 1 fibers, 35% type 2A fibers, and 53% type 2B fibers, whereas control sternohyoid muscle consisted of 4% type 1 fibers, 27% type 2A fibers, and 69% type 2B fibers. Chronic episodic hypoxia had no effect on fiber-type distribution of either muscle.



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  		Figure 5. Geniohyoid (left) and sternohyoid (right) fiber-type distribution in control rats (n = 8) and rats with chronic intermittent hypoxia (n = 8).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
OSA is a major clinical disorder in which the UA undergoes episodes of collapse during sleep.1 2 3 The causes of this failure to maintain UA patency are poorly understood, but since the contraction of UA muscles dilates and stabilizes the UA,1 2 3 dysfunction of UA muscle contraction is strongly implicated in the pathogenesis of the condition. Abnormalities of sternohyoid and geniohyoid structure have been observed in the English bulldog, an animal model of human OSA and11 abnormalities in a variety of other UA muscles have been observed also in humans with OSA.12 13 15 In all of these studies, an increase in fast-twitch fibers was reported, and this has been suggested to be due to chronically increased activity and force generated in the UA muscles.14 It has been suggested also that these changes may lead to alterations of UA muscle function and a vicious cycle of further UA collapse resulting in further UA muscle dysfunction.14 However, little is known about UA muscle contractile function in OSA, although Series et al12 showed that musculus uvulae contractile properties including fatigue were similar in subjects with OSA and in snorers.

Another mechanism whereby such changes in UA muscles might take place is through the effects of hypoxia. The effects of chronic continuous hypoxia on skeletal muscle structure and function are controversial. Chronic hypobaric hypoxia was reported to have no effect on soleus muscle structure in rats19 or guinea pigs.20 Similar results were obtained by Ishihara et al21 in adult rats, but an increase in fast fibers was observed if exposure to hypoxia occurred during development. Bigard et al16 also obtained the same results for soleus muscle in adult rats, but these workers reported that chronic hypoxia caused an increase in fast fibers in the extensor digitorum longus and plantaris muscle. Therefore, this raises the possibility that the increase in fast fibers observed in the UA muscles in OSA might be caused by hypoxia, and such an effect would likely result in alterations in UA muscle contractile properties.

The effects of chronic intermittent hypoxia on skeletal muscle structure or function have not been previously investigated. In the present experiments, we report that chronic intermittent hypoxia had no effect on twitch or tetanic tension, contractile kinetics, or tension-frequency relationship of both sternohyoid and geniohyoid muscles, and this was consistent with the absence of an effect on fiber-type distribution in either muscle. The values reported here for fiber-type distribution agree well with those of Bracher et al.22 The absence of an effect of chronic intermittent hypoxia on contractile kinetics is consistent with the finding that chronic continuous hypoxia has no effect on rat extensor digitorum longus and soleus contraction or half-relaxation time.23 However, in the latter study, twitch and tetanic tension were reduced, whereas these values were unaffected in the present experiments. However, there was a significant increase in fatigue in both muscles following chronic episodic hypoxia treatment. It is difficult to speculate on the cause of this since the causes of fatigue are complex and poorly understood. Clearly, it is not due to a fiber-type transition. Fatigue is thought to result from a progressive decline in calcium release from the sarcoplasmic reticulum,24 which can be caused by intracellular H+ accumulation.25 Acute hypoxia exacerbates fatigue and decreases muscle pH,25 but the effects of repetitive hypoxia are not known. An alternative possibility might involve reactive oxygen species. This is because reactive oxygen species increase fatigue,26 and chronic continuous hypoxia has been shown to increase antioxidant enzyme concentrations, indicative of excess oxygen-derived free-radical production.27 Whatever the mechanism of increased fatigue, we propose that this effect might have implications for the pathogenesis of OSA. Thus, the chronic episodic hypoxia of OSA could lead to increased vulnerability of the UA muscles to fatigue, leading to further hypoxia and a vicious cycle exacerbating the condition. Since UA muscles have a relatively high content of fast-twitch fibers,3 22 28 and since the activity in these muscles is high in patients with OSA,14 29 these muscles may be particularly vulnerable to fatigue. It has been suggested that this vulnerability may be further exacerbated by acute hypoxia during UA occlusion since UA muscle activity is very high, and since acute hypoxia has been shown to reduce geniohyoid endurance.30

In conclusion, these results show that chronic intermittent hypoxia increases fatigue in rat geniohyoid and sternohyoid muscles. Since chronic intermittent hypoxia is a consequence of UA muscle dysfunction, we propose that increased UA muscle fatigue could lead to a positive feedback of further loss of ability to maintain UA patency, further hypoxia, and further UA muscle dysfunction.


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


   Footnotes
 
Abbreviations: ATPase = adenosine triphosphatase; OSA = obstructive sleep apnea; UA = upper airway

Supported by the Royal College of Surgeons in Ireland.

Received for publication August 11, 2000. Accepted for publication March 25, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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