Calcineurin is not involved in some mitochondrial enzyme adaptations to endurance exercise training in rat skeletal muscle

Terada, Shin; Nakagawa, Hisashi; Nakamura, Yoshio; Muraoka, Isao

doi:10.1007/s00421-003-0858-7

Cited by 14 publications

(9 citation statements)

References 41 publications

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“…This finding is in keeping with the observation by Terada et al (60) that cyclosporin treatment did not prevent the increases in muscle citrate synthase and 3-hydroyacyl-CoA dehydrogenase activities induced by exercise. It also fits with the conclusion that the increase in mitochondrial biogenesis induced by raising cytosolic Ca 2ϩ in L6 myotubes is mediated by CaMK, as evidenced by the finding that the CaMK inhibitor KN93 completely prevents the increase in mitochondria (47).…”

Section: Discussionsupporting

confidence: 82%

Role of calcineurin in exercise-induced mitochondrial biogenesis

García-Rovés

Huss²,

Holloszy³

2006

American Journal of Physiology-Endocrinology and Metabolism

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Raising cytosolic Ca2+induces an increase in mitochondrial biogenesis in myotubes. This phenomenon mimics the adaptive responses of skeletal muscle to exercise. It has been hypothesized that increases in cytosolic Ca2+during motor nerve activity stimulate mitochondrial biogenesis by activating calcineurin. Overexpression of constitutively active calcineurin increases expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and induction of genes involved in mitochondrial energy metabolism in muscle cells. The purpose of this study was to determine whether calcineurin plays a role in the stimulation of mitochondrial biogenesis by exercise. Rats were exercised on 5 successive days by means of swimming. Inhibition of calcineurin with cyclosporin did not prevent the exercise-induced increases in PGC-1α and a range of mitochondrial proteins. In contrast to the other mitochondrial proteins, the increases in cytochrome oxidase (COX)-I and -IV proteins were blocked by cyclosporin treatment. This inhibitory effect of cyclosporin occurred at the posttranscriptional level, as evidenced by normal increases in COX-I and COX-IV mRNAs in response to exercise in the cyclosporin-treated rats. This toxic effect of cyclosporin may account for the decrease in muscle respiratory capacity reported to occur with cyclosporin treatment. In conclusion, inhibition of calcineurin does not prevent the exercise-induced increase in mitochondrial biogenesis in skeletal muscles, providing evidence that the adaptive response is not mediated by activation of calcineurin.

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Section: Discussionsupporting

confidence: 82%

Role of calcineurin in exercise-induced mitochondrial biogenesis

García-Rovés

Huss²,

Holloszy³

2006

American Journal of Physiology-Endocrinology and Metabolism

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“…9,10 In the present study, CsA treatment did not alter skeletal muscle mitochondrial enzyme activities, including those of MDH and CS, thus suggesting that calcineurin may not be a candidate for regulating mitochondrial enzyme activity through a Ca 2+ -dependent pathway. Although our results agreed with those of some previous studies, 4,5,28 another study demonstrated that CsA treatment for over 4 weeks decreased succinate dehydrogenase activity of type I, IIX and IIB fibres in rat EDL muscle. 40 Conversely, other studies have also demonstrated that CsA treatment for 3 weeks significantly increases the CS activity of rat soleus muscle.…”

Section: Discussioncontrasting

confidence: 59%

“…Both the present and a previous study 28 have demonstrated that HK activity increased after the inhibition of calcineurin in slowtwitch soleus muscle, but not in fast-twitch muscle. It is speculated that calcineurin may play a role in suppressing skeletal muscle HK activity.…”

Section: Discussionsupporting

confidence: 46%

Inhibition of calcineurin increases monocarboxylate transporters 1 and 4 protein and glycolytic enzyme activities in rat soleus muscle

Suwa

Nakano

Kumagai

2005

Clin Exp Pharma Physio

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1. The present study was designed to examine the role of calcineurin in muscle metabolic components by the administration of the specific calcineurin inhibitor cyclosporine A (CsA) to rats. 2. Male Wistar rats were divided into either a CsA-treated group (CT) or a vehicle-treated group (VT). Cyclosporine A was administered subcutaneously to rats at a rate of 25 mg/kg bodyweight per day for 10 successive days. Thereafter, changes in muscle enzyme activities and glucose transporter (GLUT)-4 and monocarboxylate transporter (MCT)-1 and MCT-4 proteins in the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles were examined. 3. There was a significant increase in MCT-1 and MCT-4 proteins in the soleus muscle in the CT group, but not in the EDL muscle. The activities of hexokinase, pyruvate kinase and lactate dehydrogenase in the soleus muscle also increased significantly in the CT group, but a similar increase in enzyme activity was not seen in EDL muscle. The activities of citrate synthase or malate dehydrogenase and the GLUT-4 protein content were not altered by CsA treatment in either the soleus or EDL muscles. 4. These results seem to imply that calcineurin negatively regulates the components of glucose/lactate metabolism, except for GLUT-4, especially in slow-twitch muscle.

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“…Alternative pathways, such as the aforementioned calcineurin signaling pathway (44), may play a critical role in mediating exercise training-induced increases in mitochondria. However, recent reports have questioned the involvement of calcineurin in these training adaptations (45,46). Clearly, more studies are needed to comprehensively understand the mechanisms leading to exercise traininginduced mitochondrial biogenesis.…”

Section: Discussionmentioning

confidence: 99%

Skeletal Muscle Adaptation to Exercise Training

et al. 2007

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1Regular endurance exercise has profound benefits on overall health, including the prevention of obesity, cardiovascular disease, and diabetes. The objective of this study was to determine whether AMP-activated protein kinase (AMPK) mediates commonly observed adaptive responses to exercise training in skeletal muscle. Six weeks of voluntary wheel running induced a significant (P < 0.05) fiber type IIb to IIa/x shift in triceps muscle of wild-type mice. Despite similar wheel running capacities, this traininginduced shift was reduced by ϳ40% in transgenic mice expressing a muscle-specific AMPK␣2 inactive subunit. Sedentary mice carrying an AMPK-activating mutation (␥1TG) showed a 2.6-fold increase in type IIa/x fibers but no further increase with training. To determine whether AMPK is involved in concomitant metabolic adaptations to training, we measured markers of mitochondria (citrate synthase and succinate dehydrogenase) and glucose uptake capacity (GLUT4 and hexokinase II). Mitochondrial markers increased similarly in wild-type and AMPK␣2-inactive mice. Sedentary ␥1TG mice showed a ϳ25% increase in citrate synthase activity but no further increase with training. GLUT4 protein expression was not different in either line of transgenic mice compared with wild-type mice and tended to increase with training, although this increase was not statistically significant. Training induced a ϳ65% increase in hexokinase II protein in wild-type mice but not in AMPK␣2-inactive mice. Hexokinase II was significantly elevated in sedentary ␥1TG mice, without an additional increase with training. AMPK is not necessary for exercise training-induced increases in mitochondrial markers, but it is essential for fiber type IIb to IIa/x transformation and increases in hexokinase II protein. Diabetes

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Calcineurin is not involved in some mitochondrial enzyme adaptations to endurance exercise training in rat skeletal muscle

Cited by 14 publications

References 41 publications

Role of calcineurin in exercise-induced mitochondrial biogenesis

Role of calcineurin in exercise-induced mitochondrial biogenesis

Inhibition of calcineurin increases monocarboxylate transporters 1 and 4 protein and glycolytic enzyme activities in rat soleus muscle

Skeletal Muscle Adaptation to Exercise Training

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