|Year : 2014 | Volume
| Issue : 1 | Page : 78-84
Effect of experimental hyperthyroidism on the maximum acute exercise tolerance and neuromuscular performance in rats
Safaa El-Kotb, Yahya Naguib, Heba El-domiaty
Department of Clinical physiology, Faculty of medicine, El Menoufia University, Yassin Abd El Ghaffar street, Shebin El Kom, 32511 El Menoufia, Egypt
|Date of Submission||07-Mar-2013|
|Date of Acceptance||05-Jun-2013|
|Date of Web Publication||20-May-2014|
MD, El-nady Street, Tanta
Source of Support: None, Conflict of Interest: None
Thyroid hormones regulate many physiologic functions such as energy and heat production, synthesis of proteins, and muscle contraction.
This study aims to demonstrate the mechanism by which hyperthyroidism affects neuromuscular performance and acute exercise tolerance and whether this effect is reversible or not after recovery in rats.
Materials and methods
Rats used in this study were divided into three groups, each containing 10 rats: (a) in the euthyroid group, rats were selected by measurement of serum FT3 (triiodothyronin), FT4 (tetraiodothyronine), and thyroid-stimulating hormone levels. (b) In the hyperthyroid group, hyperthyroidism was induced by Eltroxin in increasing doses, beginning from 50 μg to reach 200 μg/kg body weight daily by intragastric administration for 3 weeks. (c) In the recovery group, hyperthyroid rats are allowed to recover by exogenous thyroxine withdrawal for 25 days. After induction, body weight and the maximal swimming time were estimated, and then retro-orbital blood samples were collected for estimation of malondialdehyde and the total antioxidant capacity. Rats were then killed by cervical decapitation. Phrenic nerve diaphragm preparations were excised, connected to a four-channel oscillograph for measuring the strength of muscle contraction at the start of the experiment and after 30 min activity using both direct and indirect stimulation. Glucose uptake by the muscle during 30 min of activity and 30 min of recovery was estimated.
The data show that hyperthyroidism induced by Eltroxin elevates serum malondialdehyde significantly when compared with the euthyroid group, whereas reduces total antioxidant capacity significantly. Hyperthyroidism was also associated with reduction of body weight, the maximal swimming time, the strength of skeletal muscle contraction induced by direct and indirect repetitive stimulation, and its glucose uptake.
Oxidative stress plays a critical role in the pathogenesis of hyperthyroidism, especially on skeletal muscle performance and exercise tolerance. This effect is reversible after restoration of the euthyroid state.
Keywords: Eltroxin, exercise, hyperthyrodism, neuromuscular performance
|How to cite this article:|
El-Kotb S, Naguib Y, El-domiaty H. Effect of experimental hyperthyroidism on the maximum acute exercise tolerance and neuromuscular performance in rats. Menoufia Med J 2014;27:78-84
|How to cite this URL:|
El-Kotb S, Naguib Y, El-domiaty H. Effect of experimental hyperthyroidism on the maximum acute exercise tolerance and neuromuscular performance in rats. Menoufia Med J [serial online] 2014 [cited 2020 Feb 20];27:78-84. Available from: http://www.mmj.eg.net/text.asp?2014/27/1/78/132754
| Introduction|| |
Thyroid hormones accelerate the basal metabolic rate and oxidative metabolism by the induction of specific mitochondrial enzymes, by the acceleration of reactive oxygen species (ROS) production and by inducing changes in the antioxidant protective systems of various tissues . Radical reactions are chain reactions. The radicals are generated in a single step or steps called initiation. They participate in a sequence called propagation reactions in which their number increases. Finally, a process called termination destroys them. Accumulating evidence has suggested that the hypermetabolic state in hyperthyroidism is associated with increased free radical production and lipid peroxide levels . Despite the well-accepted view that loss of muscle strength and exercise intolerance are prominent clinical features of hyperthyroid patients, the mechanisms underlying the decreased capacity of contractile function in the skeletal muscle remain incompletely understood . Although protein degradation due to accelerated proteolysis has been found in the skeletal muscle of patients with hyperthyroidism, it seems unlikely that the protein loss contributes only to the muscle weakness in hyperthyroid skeletal muscles. Mainly on the basis of clinical examinations, muscle strength has been shown to be decreased by 40-100%, whereas muscle mass reduced by only 20% in hyperthyroidism. This suggests that the observed reduction in force may result not only from muscle atrophy but also from failure in the excitation-contraction coupling process . Thyroxine is responsible for the degradation of muscle fibers specifically at the motor end plates. There is a debate as to whether thyroxine degrades the motor end plates from the muscular side, from the nervous system side, or a combination of both . Decreased levels of acetylcholinesterase was observed within the neuromuscular junction . This stimulates the MEP of the muscle fiber. Overstimulation of motor end plate (MEP) could cause more muscle contractions, which eventually evoke muscle fiber fatigue, weakness, and finally degradation. The impaired sarcoplasmic reticulum (SR) function is associated with hyperthyroidism as a major contributor to the depression in force induced by exercise to exhaustion. Thyroxine directly causes a reduction in the protein kinase affinity to cAMP within muscle fibers. Treatment for hyperthyroidism (pharmacologic therapy, radioactive iodine treatment, and surgery) has been shown to be effective in improving muscle function and restoring body composition. However, these changes are time dependent. The improved muscle performance seen with the treatment of hyperthyroidism is due to enhanced intrinsic muscle function and improved muscle mass.
| Materials and methods|| |
This study was carried out on 30 adult male albino rats (150-200 g). Rats were housed in fully ventilated cages (10 rats/cage). The size of the cage was 60 × 60 × 25 cm, with free access to water and diet throughout the study period in the animal house of Menoufia Faculty of Medicine under an artificial light/dark cycle of 12 h. The animals were divided into three groups: (a) the euthyroid group (n = 10 rats): rats were selected as euthyroid by measuring the serum FT3, FT4, and thyroid-stimulating hormone (TSH) levels. They were given 0.5 ml physiological saline daily intragastrically. (b) The hyperthyroid group (n = 10 rats): hyperthyroidism was induced by exogenous thyroxine (T4) in increasing doses, beginning with 50 μg to reach 200 μg/kg body weight daily by intragastric administration for 3 weeks. Eltroxin tablets were dissolved in 0.5 ml physiological saline and rats were given 50 μg/kg body weight Eltroxin during the first week; the dose was then increased to 100 μg/kg body weight during the second week, and then to 200 μg/kg body weight during the third week . (c) The recovery group (n = 10 rats): hyperthyroid rats are allowed to recover by withdrawal of thyroxine administration for 25 days . Recovery of the rats was confirmed by repetitive laboratory measurement of serum FT3, FT4, and TSH levels.
The body weight of all rats was determined at the start and the end of the experiment.
Chemicals used for the preparation of the Krebs-Henseleit solution More Details were purchased from Sigma (St Louis, Missouri, USA). Eltroxin (50 mg tablet) were from Glaxo Wellcome; Boehringer Mannheim, Germany. Kits for the estimation of serum T3, T4, and TSH and kits for the estimation of serum glucose were from Boehringer Mannheim (Germany) kits for the estimation of serum malondialdehyde (MDA) were from Cayman Chemical (Cayman chemical San Diego, California, USA), and kits for the estimation of serum total antioxidant capacity (TAC) were from Cayman Chemical.
Maximal swimming time
Rats were acclimated to swimming for 10 min daily for 2 days in a water tank (diameter, 40 cm; depth, 70 cm) at a temperature of 35 ± 1°C . The maximum swim time in rats subjected to acute forced swimming was measured by forcing the animals to swim against load (5% of body weight) attached ∼2 inches from the end of the tail . The swimming time was measured from the beginning of swimming with the weights until the rats could not again return to the surface of the water 10 s after sinking. Then the animals were helped out of the water and returned to their home cage for recovery .
Blood sampling and biochemical analysis
Retro-orbital blood samples (2 ml each) were obtained through heparinized capillary tubes. Samples were allowed to clot at room temperature in a water bath for 15 min. The supernatant serum was collected in a dry tube . Serum samples were used for the estimation of FT3, FT4, TSH, and serum MDA and TAC.
Phrenic nerve diaphragm preparation
After cervical decapitation, the frontal part of the skin and the right thoracic wall were removed. An incision was made just above the frontal insertion of the diaphragm; the frontal part of the left thoracic wall was then removed and the phrenic nerve was seen quite distinctly after removing the left lung. The left abdominal muscles were cut along the costal margin and the last rib was held with a pair of forceps. The strip was cut out beyond the tendinous part with about 2.5 cm of phrenic nerve attached to it. The preparation had a fan-like shape. Then, the preparation was attached to a standard plastic diaphragm electrode through the costal margin while the central tendon was connected through a thread to an isometric transducer to the four-channel oscillograph . The nerve was laid over a pair of platinum electrodes, and the plastic holder was wired suitably to allow independent direct stimulation of the muscle through platinum electrodes. The preparation was left to rest for about 30 min in normal Krebs solution  before measuring the following parameters.
The strength of muscle contraction
It was measured at the start of the experiment and after 30 min activity using both direct and indirect stimulation. Supramaximal electric shock was used at a rate of 2/s and an intensity of 50 V. This rate gives steady contraction for 30 min .
Glucose uptake by the muscle
It was measured after 30 min of activity and after 30 min of recovery. Three samples were taken from bathing Krebs solution; the first sample was taken at the start of the experiment, the second sample was taken after 30 min of activity of the diaphragmatic muscle, and the third sample was taken after 30 min of recovery. Their glucose levels were estimated by the glucose oxidase method .
Glucose uptake was calculated using the following formulae:
- Glucose uptake during 30 min activity = sample (l)−sample (2).
- Glucose uptake during 30 min recovery = sample (2)−sample (3).
Then, the glucose uptake was calculated for each gram of tissue by dividing glucose uptake (mg) by the weight of the muscle (g/tissue).
It was performed by the Kruskal-Wallis one-way analysis of variance for multiple comparisons followed by Fisher's test (SPSS version 12. Medical biostatistics, Delhi, India, Marcell Dekien). Values are expressed as mean ± SD. The Post-hoc Scheffe test was applied to identify the source of statistical significance. P-values of less than 0.05 were considered statistically significant.
| Results|| |
The data of the present investigation revealed that Eltroxin administration caused a statistically significant elevation of FT3, FT4, and serum MDA. It also caused a significant reduction in TSH, the TAC level, body weight, the maximal swimming time, the strength of skeletal muscle contraction caused by direct and indirect repetitive stimulation, and its glucose uptake.
[Figure 1] shows that the mean value of FT3 was 8.83 ± 0.8 pg/ml, that of FT4 was 4.1 ± 0.63 ng/ml, and MDA was 3.65 ± 0.34 mmol/l in hyperthyroid rats, which were significantly (P < 0.01) higher, whereas the mean value of TSH was 0.061 ± 0.005 mIU/ml and TAC was 0.43 ± 0.08 mmol/ml, which were significantly (P < 0.01) lower than the corresponding values in euthyroid rats. The figure also shows that the effect of recovery on the mean value of FT3 was 3.43 ± 0.26 pg/ml, that of FT4 was 1.07 ± 0.13 ng/ml, and MDA1.27 ± 0.2 mmol/l in hyperthyroid recovered rats, which were significantly (P < 0.01) lower, whereas the mean value of TSH and TAC (1.26 ± 0.06 mmol/l) were significantly (P < 0.01) higher than the corresponding values in hyperthyroid rats
[Figure 2] shows that the mean values of body weight at the end of the experiment was 210.25 ± 6.36 g and maximum swim time (MST) was 14.39 ± 1.32 min in the hyperthyroid rats, which were significantly (P < 0.01) lower than the corresponding values in euthyroid rats. The figure also shows that the effect of recovery on the mean value of body weight at the end of the experiment was 235.25 ± 5.56 g and MST was 22.18 ± o.60 min in the hyperthyroid recovered rats, which were significantly (P < 0.01) higher than the corresponding values in hyperthyroid rats. The figure also shows that the mean values of glucose uptake during 30 min of activity and 30 min of recovery were 3.53 ± 0.11 and 1.67 ± 0.10 mg/g tissue, which were significantly (P < 0.01) lower than the corresponding values in euthyroid rats. The figure also shows that the effect of recovery on the mean value of glucose uptake during 30 min of activity and 30 min of recovery were 4.69 ± 0.09 and 2.70 ± 0.09 mg/g tissue, which were significantly (P < 0.01) higher than the corresponding values in hyperthyroid rats.
[Figure 3] shows representative examples of the strength of the muscle contraction (g/tension), caused by direct and indirect repetitive electrical stimulation (2/impulse/s) in all study groups. The figure shows the mean values of the strength of muscle contraction at the onset of the experiment both direct and indirect to be 2.93 ± 0.28 and 2.16 ± 0.12 g/tension, respectively, in hyperthyroid rats, which were significantly (P < 0.01) lower; also, after 30 min of activity, the strength of muscle contraction using both direct and indirect stimulation were 2.03 ± 0.14 and 1.4 ± 0.12 g/tension, which were significantly (P < 0.01) lower than the corresponding values in euthyroid rats. The figure also shows that the effect of recovery on the mean value of the strength of muscle contraction at the onset of the experiment both direct and indirect were 3.77 ± 0.12 and 3.13 ± 0.04 g/tension, respectively, in hyperthyroid recovered rats, which were significantly (P < 0.01) higher; also, after 30 min of activity, the strength of muscle contraction using both direct and indirect stimulation were 2.53 ± 0.07 and 2.033 ± 0.08 g/tension, which were significantly (P < 0.01) higher than the corresponding values in hyperthyroid rats.
| Discussion|| |
Hyperthyroidism is a pathologic syndrome in which tissue is exposed to excessive amounts of circulating thyroid hormones. One important component of hyperthyroid-induced myopathy is atrophy, and it is a contributing factor for the reduction in absolute muscle strength and functional capacity . Eltroxin administration resulted in a statistically significant increase in the serum level of T3 and T4, with significant reduction in the serum level of TSH. Eltroxin, especially when taken with food, once absorbed is indistinguishable from the endogenous hormone. It is nearly totally bound to serum proteins and has an elimination half-life of 6-7 days in Euthyroid rats. This was supported by Liu et al.  and Ahmed et al. . Eltroxin also decreased the strength of skeletal muscle contraction (direct and indirect) both at the onset of the experiment and after 30 min of activity, and also decreased the maximal swimming time and body weight. These findings could be explained by the observable significant increase in serum MDA and significant decrease in serum TAC. Hyperthyroidism is a hypermetabolic state accompanied by increased oxygen utilization, increased production of ROS, and consequently measurable changes in antioxidative factors. This hypermetabolic state is associated with tissue oxidative injury and lipid peroxidation in slow oxidative muscles. Also, protein oxidation could play an important role in the etiology of contractile dysfunctions in hyperthyroidism because oxidative stress, as mediated by vigorous contractile activity, can modify the structure and function of proteins associated with excitation-contraction coupling. These result was in agreement with Mishra and Samanta , who reported that hyperthyroidism accelerates ROS generation and produces changes in the antioxidant systems of various tissues; this chronic increase in the cellular levels of ROS can lead to a catastrophic cycle of DNA damage, mitochondrial dysfunction, further ROS generation, and cellular injury. In agreement with our results, Yamada et al.  found that T 3 administration induced contractile dysfunction in the diaphragm. Studies performed by Matsunaga et al.  reported that hyperthyroidism resulted in elevations in SR Ca 2+ release and uptake rates, indicating that protein oxidation has been decay SR function. The myosin heavy chain (MHC) comprises sulfhydryl-containing cysteine residues that are critical for contractile function. A single-fiber study has revealed that ROS donor-induced oxidation of sulfhydryl groups residing in the myosin head decreases isometric force production, maximal shortening velocity, and ATPase activity. Oxidation may result in a structure perturbation in myosin, leading to impaired myosin function ,. Taking these findings into consideration, it can be suggested that elevated ROS production may contribute to the hyperthyroid-induced force reduction by modulating the structural state of MHC. Yamada et al.  also reported that MHC is the most abundant protein in myofibrils, and it is highly susceptible to oxidation in hyperthyroidism. Callahan et al.  found that hyperthyroidism increases lipid peroxidation, MDA, and hydroperoxides in mouse skeletal muscle during hyperthyroidism. In the present investigation, Eltroxin administration caused significant decrease in glucose uptake by skeletal muscles during 30 min of activity and 30 min of recovery. There is a preferential increase in lactate formation relative to glucose oxidation in the skeletal muscle. This is supported by a study on rats reporting that in the fed state, hyperthyroidism increased glucose utilization in the skeletal muscle but decreased the activity of the pyruvate dehydrogenase complex, a key enzyme for the regulation of glucose oxidation ,. In this study suggesting the presence of insulin resistance, hyperthyroidism is associated with an increase in the secretion of GH and glucocorticoids in vivo. Changes in the levels of these hormones in plasma affects glucose homeostasis. Hyperthyroidism increases the secretion of bioactive mediators (adipokines) such as interleukin 6 and tumor necrosis factor a from adipose tissues. These adipokines exert both proinflammatory and insulin-resistant effects . In agreement with our results, Messarah et al.  showed a significant animal body weight loss in hyperthyroidism compared with controls, and food consumption increased by 27% in hyperthyroid rats. Yamada et al.  also reported a marked decrease in the body weight of hyperthyroid rats. Regarding the maximum acute exercise tolerance, Casimiro-Lopes et al.  reported that hyperthyroidism in rats reduced the exercise capacity markedly through its known effects on glycogen metabolism. They reported that hyperthyroid rats showed low glycogen content in the skeletal muscle and liver and low leptin levels while corticosterone was higher. Kahaly et al.  also reported that the muscle performance is reduced, with accumulation of lactic acid during exercise and acceleration of glycolysis, in hyperthyroidism. Mitochondria oxidative dysfunction during exercise in thyroid dysfunction causes intracellular acidosis. These abnormalities partly explain why subjects with dysthyroidism are intolerant to exertion.
The present investigation showed that the withdrawal of thyroxine administration resumed normal thyroid function tests after 25 days of withdrawal. These results are supported by Rao et al. , who reported that when hyperthyroid rats were allowed to recover for 17 days after treatment with thyroxine, thyroid function tests returned to values indistinguishable from the control. Also, withdrawal caused significant increase in the strength of skeletal muscle contraction (direct and indirect) at the onset of the experiment and after 30 min of activity, glucose uptake by skeletal muscle during 30 min of activity and 30 min of recovery, the maximal swimming time, the body weight, the serum TAC, and the level of serum MDA. These data suggest that the effect of the significant decrease of the neuromuscular performance, glucose uptake by skeletal muscle, exercise tolerance, and oxidative stress markers is reversible. In agreement with our results, Santo et al.  showed that the muscle mass and the muscle strength tend to increase after the achievement of a euthyroid state. Besides improving muscle performance, treatment for hyperthyroidism is directed toward restoring body weight to normal values. Also, Moura et al.  reported that the treatment of hyperthyroidism and rendering patients in the euthyroid status resulted in a significant increase in the body weight, the BMI, the fat mass, the fat-free mass, and the thigh muscle area. They also reported that the treatment of overt hyperthyroidism results in the reduction of whole-body fluxes of leucine and phenylalanine, indicating a reduction in the protein turnover at the whole-body level. Moreover, changes in mRNA levels of MHC isoforms suggest that hyperthyroidism has differential effects on individual muscle proteins with a clear tendency to promote fast-twitch muscle action. These changes in protein metabolism and muscle mRNA levels occurred in association with substantial changes in both muscle performance and energy metabolism. Amara et al.  expected that the protection of organs against oxidation-induced damage may prevent or inhibit decreases in tension developed by human skeletal muscles. Also, antioxidants are capable of offsetting the effects of ROS. Al-Shoumer et al.  reported that abnormal glucose metabolism returned to normal as early as 4 weeks after initiation of antithyroid therapy. Roubsanthisuk et al.  also reported that after the treatment of hyperthyroidism till achieving a euthyroid state, the majority of cases showed an improvement in glucose tolerance.
| Acknowledgements|| |
Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3]