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coactivator-1
of fibres in the soleus muscle of Zucker diabetic fatty rats1 Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan 2 Laboratory of Metabolism5 Laboratory of Neurochemistry, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan 3 Diabetic Center, Tsunashimakai-Kosei Hospital, Himeji, Japan 4 Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
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Abstract |
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coactivator-1
(PGC-1), and the oxidative enzymes in mitochondria, exemplified by succinate dehydrogenase (SDH), were changed in type I and II muscle fibres in each type of rat, using the new technique of laser capture microdissection (LCM). Both plasma glucose and glucosylated haemoglobin levels were significantly higher in ZDF than in ZL and ZF rats. A lower percentage of type IIA fibres was observed in the muscles of ZDF rats than in those of ZL and ZF rats. The mRNA expression levels of SDH in type II fibres and of PGC-1 in type I fibres were significantly lower in ZDF than in ZL and ZF rats as assessed by LCM and real-time PCR analysis. We have shown, for the first time, that a lower percentage of type IIA fibres was observed in ZDF rats. We have also discovered that the expression levels of the oxidative metabolism-related genes, PGC-1 and SDH, decreased in type I and type II fibres, respectively, of ZDF rats.
(Received 13 August 2006;
accepted after revision 6 December 2006; first published online 7 December 2006)
Corresponding author T. Adachi: Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan. Email: adachi-tet{at}umin.ac.jf
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Introduction |
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Mammalian skeletal muscles are comprised of several types of fibres based on their metabolic and contractile properties (Brooke & Kaiser, 1970; Peter et al. 1972). There are two major classifications of the fibre type: slow-twitch type I and fast-twitch type II. The soleus muscle in rats has three fibre types: type IIA and type IIC, both of which are subtypes of type II fibres, and type I. Several studies (Mårin et al. 1994; Hickey et al. 1995; Nyholm et al. 1997) have reported that the skeletal muscles of patients and animal models with type 2 diabetes mellitus show lower oxidative enzyme activity than normal. The alteration of fibre distribution and fibre specific glycolytic and oxidative enzyme activity in skeletal muscle of patients with type 2 diabetes has been reported (Oberbach et al. 2006). Especially in the soleus muscle, in which fibre oxidative activity is normally high, the oxidative metabolism of glucose and lipids in patients and animal models with type 2 diabetes mellitus is low (Hickey et al. 1995). Recently, we have found that obese Otsuka Long–Evans Tokushima Fatty (OLETF) rats and non-obese Goto-Kakizaki (GK) rats, which are animal models that develop type 2 diabetes mellitus, have a lower percentage of type IIA fibres than age-matched non-diabetic rats (Yasuda et al. 2001, 2002, 2006). These results indicate that the fibre type specific oxidative metabolism is related to the pathology of skeletal muscle in type 2 diabetes.
Oxidative metabolism of glucose and lipids in muscle fibres is regulated by transcriptional factors of metabolic genes, such as peroxisome proliferator-activated receptor- coactivator-1 (PGC-1; Wende et al. 2005). PGC-1 coactivates peroxisome proliferator-activated receptors (PPARs), which control metabolic homeostasis (Puigserver, 2005). Succinate dehydrogenase (SDH) is one of the mitochondrial oxidative enzymes in skeletal muscle. It controls transcription of metabolism-related genes in mitochondria and promotes metabolism of glucose and lipids. Succinate dehydrogenase is known to be related to oxidative metabolism in skeletal muscle. In the skeletal muscles of patients and animal models with type 2 diabetes mellitus, the mRNA expression levels of PGC-1 and SDH have been reported to be reduced (Yechoor et al. 2002; Patti et al. 2003; Finck & Kelly, 2006). However, there are no previous reports on the expression levels of these substances in each fibre type. The isoforms and PGC-1 mRNA levels differ depending on the fibre type in the skeletal muscle, especially following exercise (Russell et al. 2003). Thus, in patients and animal models with type 2 diabetes mellitus, it is possible that the reduction in mRNA expression levels of PGC-1 and SDH inhibits oxidative metabolism and affects the pathology of skeletal muscle in type 2 diabetes.
In this study, we determined whether the change in fibre type distribution was caused by obesity alone or by diabetes. We analysed the property of each fibre type in the soleus muscle of obese, diabetic Zucker diabetic fatty (ZDF), obese, non-diabetic Zucker fatty (ZF) and non-diabetic, non-obese Zucker lean rats (ZL). In addition, to elucidate the mRNA expression levels of transcriptional factors of metabolic genes in mitochondria and the oxidative enzyme activity in each fibre type of the skeletal muscle, we sampled the RNA in type I and II fibres using laser capture microdissection (LCM), and we investigated the expression levels of transcriptional factors of metabolic genes, such as PGC-1, and of oxidative enzymes in mitochondria, such as SDH.
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Methods |
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Male ZDF, ZF and ZL rats, 4 weeks old (n = 4 in each group), were purchased from Charles River Laboratories (Wilmington, MA, USA). All rats were individually housed in similar cages and were used at 16 weeks of age in the present study. They were kept in a controlled environment with a fixed 12 h–12 h light–dark cycle (lights off from 20.00 to 08.00 h) with room temperature maintained at 22 ± 2°C. All rats were given food and water ad libitum. All experiments were approved by the University Committee for the Care and Use of Animals for research purposes, and followed the Guidelines of the National Institutes of Health for the Care and Use of Laboratory Animals.
The rats were anaesthetized with an intraperitoneal injection of sodium pentobarbitone (50 mg (kg body weight)–1), and exsanguinated. After blood sampling from the heart, soleus muscle, as well as white adipose tissue of epididymal, omental and retroperitoneal fat, were surgically removed and weighed. The total weight of the three types of white adipose tissue was taken to be the white adipose tissue weight.
Measurement of plasma glucose, HbA1c and insulin levels
Plasma obtained by centrifugation (1600g for 10 min at 4°C) was used for measurements of plasma glucose, glucosylated haemoglobin (HbA1c) and insulin levels. Plasma glucose was measured by the glucose-oxidative method (Marks 1959). Glucosylated haemoglobin was determined using the sodium lauryl sulphate–haemoglobin (SLS–Hb) method (Falco Biosystems, Kyoto, Japan). Plasma insulin was determined using ELISA (Shibayagi, Gunma, Japan) with rat insulin as the standard.
Tissue preparation
The soleus muscles on both sides were removed, cleaned of excess fat and connective tissue, and wet weighed. All rats were killed at once, a half-day after their final meal. Muscles from the left side were stored at –80°C for analysis of total SDH activity. Muscles from the right side were placed on cork, stretched to their in vivo lengths and immediately frozen in isopentane cooled in a mixture of dry ice and acetone. Serial transverse sections of the muscle, 20 µm thick, were cut in a cryostat set at –80°C for the analysis of fibre type distribution and fibre SDH activity.
Histochemical analysis
The sections were brought to room temperature, air dried for 30 min, and then stained for adenosine triphosphatase (ATPase) activity, following alkaline (pH 10.4) and acid (pH 4.5) pre-incubation (Chalmers & Edgerton, 1989a; Hirofuji et al. 2000; Nakatani et al. 2000). Fibre types were classified according to their staining intensities, following pre-incubation of glycine (pH 10.4) or barbitone acetate buffers (pH 4.5). For determination of ATPase activity, the following procedure was employed: alkaline pre-incubation in 75 mM glycine, 50 mM CaCl2 and 75 mM NaCl or acid pre-incubation in 50 mM sodium acetate and 30 mM sodium barbitone; and incubation in 2.8 mM ATP, 59 mM CaCl2 and 75 mM NaCl. After staining for ATPase activity, the sections were processed through 1% CaCl2, 2% CoCl2 and 1% (NH4)2S, and dehydrated through a graded ethanol series, followed by two changes in xylene, and then coverslipped. The muscle fibres were classified into type I (positive with pre-incubation pH 4.5 and negative with pre-incubation pH 10.4), type IIA (negative with pre-incubation pH 4.5 and positive with pre-incubation pH 10.4) and type IIC (positive with pre-incubation pH 4.5 and 10.4). The fibre type distribution of the soleus muscle was determined from the entire transverse section of the muscle (about 500 fibres). The cross-sectional area of each fibre was measured using a computer-assisted image-processing system (Image J, NIH) for the ATPase-stained (pH 10.4) sections.
The serial sections of the soleus muscles were also stained for SDH activity, an indicator of mitochondrial oxidative potential, for 10 min at room temperature (Chalmer & Edgerton, 1989b). Activity of SDH was determined in an incubation medium containing 100 mM phosphate buffer (pH 7.5), 0.9 mM sodium azide, 0.9 mM 1-methoxyphenazine methylsulphate, 1.5 mM nitroblue tetrazolium, 5.6 mM EDTA, disodium salt, and 48 mM succinate, disodium salt. The reaction was stopped by multiple washing in distilled water. The sections were dehydrated through a graded series of ethanol followed by two changes in xylene, and then coverslipped. Histochemical control sections, in which either the succinate disodium salt or the nitroblue tetrazolium was excluded from the incubation medium, showed no positive SDH staining. The SDH activities of approximately 200 fibres from each section were determined on digitized images of the stained sections. The sections were digitized as greyscale images, and SDH staining intensity was expressed as an optical density (o.d.) value by the above-mentioned image-processing system (Ishihara et al. 1995, 1997; Yang et al. 2002). Each pixel was quantified as one of 256 grey levels. The o.d. units of all pixels within the muscle fibre were converted to a mean o.d. unit using a calibration photographic tablet, which calibrated 21 gradient density range steps and their diffused density values.
Soleus muscle SDH activity
The frozen soleus muscle (20 mg) was homogenized in 100 mM phosphate buffer (pH 7.5) with a glass homogenizer at 4°C. The SDH was then demonstrated using nitroblue tetrazolium according to the method of Lojda et al. (1979) and Frederiks et al. (1986). Average optical densitometry values per microgram of protein of ZL rats for each level of SDH activity were multiplied to obtain the arbitrary value of 1.
Laser capture microdissection
After ATPase staining (pH 10.4), the sections were dehydrated in a graded series of 70, 80, 90 and 100% ethanol for 1 min each, followed by a 5 min immersion in xylene and air drying for 20 min. Laser capture microdissection was performed with the PixCell IIe (Arcturus Bioscience, Mountain View, CA, USA) as previously reported (Trogan et al. 2002), with some modifications. Briefly, 1000 capillaries were captured from each muscle fibre type. Capillaries from type I fibres or type II fibres were collected separately with CapSure LCM caps (Arcturus Bioscience).
Isolation of RNA and production of cDNA
Total RNA was extracted from captured cells using the RNeasy micro kit (Qiagen, Valencia, CA, USA), according to the manufacturer's protocols. Complementary DNAs were obtained using QuantiTect Reverse Transcription (Qiagen).
Quantification of mRNA expression level
Real-time PCR was performed using Opicon2 (Bio-Rad, Tokyo, Japan) to quantify mRNA expression levels (Adachi et al. 2005). RNA without reverse transcription was used as a negative control. The 18S rRNA primers (sense, 5'-TCAAGAACGAAAGTCGGAGGT-3'; antisense, 5'-GGACATCTAAGGGCATCACAG-3'; GenBank ID: X01117
[GenBank]
) were chosen to amplify a 489 bp fragment. Primers for PGC-1 (sense, 5'-CGGTGGATGAAGACGGATTGC-3'; antisense, 5'-CGGTGGATGAAGACGGATTGC-3'; GenBank ID: AY237127
[GenBank]
) were chosen to amplify a 312 bp fragment. Primers for SDH (sense, 5'-TGGCTTTCACTTCTCTGTTGG-3'; antisense, 5'-ATCTCCAGTTGTCCTCTTCCA-3'; GenBank ID: AB072907
[GenBank]
) were chosen to amplify a 249 bp fragment. Conditions of the PCR for amplifications were 40 cycles at 94°C for 15 s, 60°C for 30 s, and 72°C for 30 s. Each amplification sample was normalized for comparison by determining each 18S rRNA level by RT-PCR. Expression levels were quantified by generating a three-point serial standard curve. Results are expressed as fold change, determined by the ratio of calculated units of RNA in ZF and ZDF samples to those in ZL samples, presented as the means ±
S.E.M.
Statistical analysis
Results are expressed as means ± S.E.M. Statistical significance was evaluated by ANOVA, and statistical significance was defined as P < 0.05.
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The mean body weight of ZF was significantly greater than that of ZL, and there was no significant difference in mean body weight between ZDF and ZL (Table 1). There was no significant difference in mean soleus muscle weight among ZDF, ZF and ZL (Table 1). The mean adipose tissue weights of ZF and ZDF were significantly higher than that of ZL, and that of ZF was also significantly greater than that of ZDF (Table 1).
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The mean plasma glucose and HbA1c levels were significantly higher in ZDF than in ZL and ZF (Table 2). The mean plasma insulin level was significantly higher in ZF than in ZL. There was no significant difference in mean insulin level between ZL and ZDF (Table 2).
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A lower percentage of type IIA fibres and a higher percentage of type IIC fibres in the soleus muscle were observed in ZDF than in ZL and ZF (Figs 1 and 2). There was no significant difference in mean fibre type distribution between ZL and ZF (Figs 1 and 2).
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The mean SDH activity in type IIA fibres was significantly lower in ZDF than in ZL and ZF (Fig. 3A). There was no significant difference in mean fibre SDH activity between ZL and ZF (Fig. 3A). There was no significant difference in mean muscle SDH activity among ZDF, ZF and ZL (Fig. 3B).
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The mRNA expression level of SDH in type II (type IIA and IIC) fibres was significantly lower in ZDF than in ZL and ZF (Fig. 4B), while there was no significant difference in mRNA expression level of SDH in type I fibres among ZL, ZL and ZDF (Fig. 4A). There was no significant difference in mRNA expression levels of PGC-1 in type II fibres among ZL, ZL and ZDF (Fig. 4D). The mRNA expression level of PGC-1 in type I fibres was significantly lower in ZDF than in ZL and ZF (Fig. 4C).
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Discussion |
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and SDH in type I and II muscle fibres in each rat, using LCM. This is the first study to examine the fibre type distribution and the mRNA expression in each fibre in diabetic and obese animals. First, we analysed the characteristics of the diabetic and obese rats. The body weight of ZF was higher than that of ZL (Table 1). In contrast, adipose tissue weight of ZF and ZDF was higher than that of ZL (Table 1). There was a significantly higher level of plasma insulin in ZF, with no significant difference between ZDF and ZL rats (Table 2). Plasma glucose and HbA1c were increased in ZDF compared with ZL and ZF (Table 2). These characteristics are almost consistent with the previously reported data (Finegood et al. 2001; Wang et al. 2001; Oana et al. 2005; Nakano et al. 2006). These factors suggest that ZF exhibits only obesity and ZDF exhibits hyperglycaemia and diabetes at 16 weeks of age.
Soleus muscle weight was not significantly different among ZDF, ZF and ZL (Table 1). These results suggest that soleus muscle weight may not change in obesity and diabetes. In contrast, a lower percentage of type IIA fibres was observed in ZDF than in ZL, while the fibre type distribution in the soleus muscle of ZF rats had similar distribution compared with that of ZL rats (Figs 1 and 2). Our previous studies (Yasuda et al. 2001, 2002, 2006) reported that the fibre type distribution of the soleus muscle of both obese OLETF and non-obese GK rats had a lower percentage of high-oxidative type IIA fibres. These results indicate that the shift in type of muscle fibres occurs only in diabetic ZDF rats.
In several studies (Mårin et al. 1994; Hickey et al. 1995; Nyholm et al. 1997), disordered metabolic properties specific to the fibre type in the skeletal muscles of patients and animal models with type 2 diabetes mellitus have been reported, especially with regard to high-oxidative fibres. In the present study, the type shift of muscle fibres was observed in the soleus muscle of diabetic ZDF rats (Figs 1 and 2). We also found a lower percentage of type IIA fibres and lower oxidative enzyme activity in type IIA fibres of diabetic ZDF rats (Fig. 3A). However, there was no significant difference in muscle SDH activity among ZDF, ZF and ZL rats (Fig. 3B). Therefore, we analysed the mRNA expression levels of SDH in type I and II fibres on ATPase-stained sections. The mRNA expression level of SDH in type II (type IIA and IIC fibres) was significantly lower in ZDF than in ZL and ZF rats (Fig. 4B), while there was no significant difference in mRNA expression level of SDH in type I fibres among ZDF, ZF and ZL rats (Fig. 4A). Therefore, it is concluded that a reduced mitochondrial oxidative capacity occurs in the soleus muscle of diabetic animals.
In this study, we have shown, for the first time, that the mRNA expression level of PGC-1 in type I fibres of the soleus muscle was significantly lower in ZDF than ZL rats (Fig. 4C). The mRNA expression level of PGC-1 is lower in the skeletal muscles of diabetic patients (Patti et al. 2003). PGC-1 is one of the nuclear proteins controlling genes that participate in energy metabolism in mammalian cells (Wende et al. 2005). The mRNA expression levels of transcriptional factors of metabolic genes in mitochondria are known to be lower than normal in the skeletal muscles of diabetic patients and model animals (Finck & Kelly, 2006). In particular, PGC-1 is reported to control metabolic pathways at the transcriptional level of gene expression, in response to environmental or hormonal stimuli (Patti et al. 2003; Puigserver, 2005; Wende et al. 2005; Finck & Kelly, 2006). Moreover, PPARs (PPAR and ) and nuclear respiratory factor 1 (NRF1) are the main transcriptional factors which are regulated by PGC-1 mRNA expression (Patti et al. 2003). If the expression level of PGC-1 in type I fibres of diabetic animals differs from that of normal animals, these substances would be key factors in the reduced pathway of oxidative capacity in the skeletal muscles of diabetic patients and animal models.
In summary, we have clarified that the percentage of high-oxidative type IIA fibres, the SDH mRNA expression level of type II fibres, and PGC-1 mRNA expression level of type I fibres were lower in ZDF than in ZL and ZF rats. These results suggest that the lower level of mRNA expression of SDH and PGC-1 in ZDF rats may affect the oxidative capacity in the soleus muscle.
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P < 0.05, 
