Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Skeletal muscle is highly adaptable, being capable of undergoing changes in its structural and functional properties in response to physiological stimuli. The fast-to-slow muscle fiber-type transition is evoked by increased motor nerve activity. Recently, the calcineurin (CaN) signaling pathway has been implicated in the transcriptional regulation of slow muscle fiber genes. Here we investigated the effect of treatment with a CaN-specific inhibitor, FK506, on skeletal muscle fiber-type transition in functionally overloaded muscles. The overloaded plantaris muscle showed fast-to-slow muscle fiber type transition, i.e., a decrease in myosin heavy chain (MHC) IIb, an increase in MHCIIa+d/x, and new expression of MHCI. In the FK506-administered group, however, overload-induced muscle fiber-type transition was completely prevented. We have demonstrated, therefore, that the CaN signaling pathway is required for fast-to-slow skeletal muscle fiber-type transition. Furthermore, we also confirmed that the protein expression levels of downstream effectors of CaN signaling exhibit a transient increase in the early phase of the overloaded condition.
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PMID:Contribution of the calcineurin signaling pathway to overload-induced skeletal muscle fiber-type transition. 1561 41

This work was undertaken to provide further insights into the expression of tropism-related genes in regenerating skeletal muscle of adult rats treated with cyclosporin-A (CsA), a calcineurin inhibitor. Rats were treated with CsA for 5 days and, on the 6th day, were submitted to cryolesion of the soleus muscles. CsA treatment continued for 1, 10, and 21 days after cryolesion. Muscles were removed, frozen, and stored in liquid nitrogen. Body and muscle weights, histological sections stained with toluidine blue, and gene expression of the regeneration molecular markers, viz., desmin and neonatal myosin heavy chain, were assessed to confirm that cryolesion and CsA treatment were effective during the allowed regeneration time. Quantitative reverse transcription/polymerase chain reaction demonstrated that myostatin gene expression was not altered by either cryolesion or CsA treatment combined with cryolesion. Calpain-3 gene expression decreased at 1 day after cryolesion and also following CsA treatment combined with cryolesion. However, calpain-3 gene expression was strongly up-regulated (approximately five-fold) 10 days after cryolesion and returned to control levels at day 21. CsA treatment blocked calpain-3 gene expression rise induced by 10 days of cryolesion. Atrogin-1 gene expression was decreased at 1 day after cryolesion and following cryolesion combined with CsA treatment, returning to control levels at day 10. These results suggest that (1) calpain-3 has a differential role in the early and late stages of regeneration in a calcineurin-dependent manner, and (2) atrogin-1 is involved in the early stages of regeneration independently of calcineurin.
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PMID:Expression of tropism-related genes in regenerating skeletal muscle of rats treated with cyclosporin-A. 1572 28

Voluntary cage wheel exercise has been used extensively to determine the physiological adaptation of cardiac and skeletal muscle in mice. In this study, we tested the effect of different loading conditions on voluntary cage wheel performance and muscle adaptation. Male C57Bl/6 mice were exposed to a cage wheel with no-resistance (NR), low-resistance (LR), or high-resistance (HR) loads for 7 wk. Power output was elevated (3-fold) under increased loading (LR and HR) conditions compared with unloaded (NR) exercise training. Only unloaded (NR) exercise induced an increase in heart mass, whereas only loaded (LR and HR) exercise training induced an increase in skeletal (soleus) muscle mass. Moreover, unloaded and loaded exercise training had a differential impact on the cross-sectional area of muscle fibers, depending on the type of myosin heavy chain expressed by each fiber. The biochemical adaptation of the heart was characterized by a decrease in genes associated with pathological (but not physiological) cardiac hypertrophy and a decrease in calcineurin expression in all exercise groups. In addition, transcriptional activity of myocyte enhancer factor-2 (MEF-2) was significantly decreased in the hearts of the LR group as determined by a MEF-2-dependent transgene driving the expression of beta-galactosidase. Phosphorylation of glycogen synthase kinase-3beta, protein kinase B (Akt), and p70 S6 kinase was increased only in the hearts of the NR group, consistent with the significant increase in cardiac mass. In conclusion, unloaded and loaded cage wheel exercise have a differential impact on cage wheel performance and muscle (cardiac and skeletal) adaptation.
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PMID:Loaded wheel running and muscle adaptation in the mouse. 1573 90

The involvement of calcineurin (CaN) and heat shock protein (Hsp) 72 in the regulation of fiber size and/or phenotype in response to functional overload (FO) was investigated. In one FO group, the plantaris muscle was overloaded by cutting the distal tendons (5-10 mm length) of the soleus and gastrocnemius of 3-week-old male Wistar rats. Cyclosporin A (CsA), a CaN inhibitor, was injected daily (5 mg/kg body weight, i.p.) in a second group of FO rats (FO+CsA group) for a 2-week period. Compared to age-matched controls (Con), the absolute and relative plantaris weights were increased in both FO groups: the hypertrophic response was attenuated in FO+CsA rats. The mean cross-sectional area of each fiber type was increased (approximately 2.0-fold) in the plantaris of FO rats: CsA treatment attenuated this effect, although the fibers were still larger than in Con rats. The percent composition of myosin heavy chain (MHC) IIb decreased from 54% in Con to 19% in FO rats, whereas types I, IIa, and IIx MHC increased in the FO rats. CsA treatment blunted the shifts in MHC isoforms: the FO+CsA group showed a smaller decrease in type IIb and a smaller increase in type IIx MHC than the FO group. The levels of CaN-A and -B proteins were higher (approximately 2.5-fold) in FO than Con rats, whereas these values were similar in Con and FO+CsA rats. Hsp72 protein levels were higher in FO (3.6-fold) and FO+CsA (5.2-fold) than Con rats, with the values being significantly higher in the FO+CsA than FO rats. CsA treatment in Con rats had no effects on muscle mass, fiber size, MHC composition, and Hsp72 or CaN levels. Combined, these results suggest that CaN levels are related to changes in both fiber size and phenotype, and that Hsp72 levels are more related to the levels of stress added to the muscle rather than to increases in the slow fiber phenotype in functionally overloaded rat plantaris muscles.
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PMID:Calcineurin and heat shock protein 72 in functionally overloaded rat plantaris muscle. 1580 55

Protein kinase B [PKB, also known as Akt (PKB/Akt)] and calcineurin (CaN) are postulated to play important roles in integrating intracellular signaling in skeletal muscle in response to disuse and increased muscle loading. These experiments investigated changes in signal transduction of the downstream pathways of PKB/Akt and CaN during recovery following disuse-induced muscle atrophy. A 10-day period of hindlimb unloading (HLU) via tail suspension (male rats) was used to produce soleus muscle atrophy. Muscle recovery was achieved by returning animals to normal ambulation for 3-10 days. HLU resulted in significant muscle atrophy and a slow-to-fast fiber transition as revealed by appearance of type IId/x and IIb myosin heavy chain (MHC) isoforms. Muscle mass in HLU animals recovered to control (Con) levels after 10 days of reloading, but the fast-to-slow shift in muscle MHC was incomplete, as indicated by the continued presence of type IId/x MHC. Ten days of HLU resulted in a significant decrease (-43%) in muscle levels of phosphorylated PKB/Akt. In contrast, muscle levels of phosphorylated PKB/Akt were greater (+56%) in HLU than in Con animals early after the onset of reloading (3 days). Soleus levels of phosphorylated p70S6K were significantly higher (+26%) in HLU animals after 3 days of muscle reloading. Muscle levels of phosphorylated PKB/Akt and phosphorylated p70S6K returned to Con levels by day 10 of recovery. Moreover, muscle CaN levels were significantly higher than Con levels after 10 days of muscle reloading. These findings are consistent with the hypothesis that PKB/Akt and its downstream mediators are active in the regrowth of muscle mass during the early periods of recovery from muscle atrophy. Our data support the concept that CaN is involved in muscle remodeling during the later phases of recovery from disuse muscle atrophy.
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PMID:Changes in PKB/Akt and calcineurin signaling during recovery in atrophied soleus muscle induced by unloading. 1582 Dec 84

In this study, we quantified the transcription of the interleukin-6 (IL-6) gene in individual fibres and the associated changes in calcineurin activity assessed at the cellular level during prolonged muscle contraction. Individual myofibres were isolated from plantaris and soleus muscles of rats at the end of an exhaustive running exercise test (n = 10), categorized according to their myosin heavy chain isoform content, and compared to those of resting rats (n = 10). Using real-time PCR analysis in individual fibres, a marked rise in IL-6 transcript levels occurred in type I and IIa fibres at the end of exercise (P < 0.05). Transcription of the gene encoding for the modulatory calcineurin-interacting protein-1 (MCIP-1), a sensitive indicator of calcineurin activity, also mainly increased in type I and IIa fibres (P < 0.05). Moreover, a slight increase in MCIP-1 mRNA levels was observed in type IIx (P < 0.05). Fibre types determined by immunohistochemistry were qualitatively examined for glycogen content using periodic acid-Shiff staining, and no direct relationship was found, at the cellular level, between glycogen content, fibre-type and IL-6 transcription. Our data clearly suggest that IL-6 gene transcription was mainly observed in early recruited myofibres and that contraction-induced IL-6 transcription could be associated with enhanced calcineurin activity.
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PMID:Fibre-type specificity of interleukin-6 gene transcription during muscle contraction in rat: association with calcineurin activity. 1590 11

Skeletal muscles are a mosaic of slow and fast twitch myofibers. During embryogenesis, patterns of fiber type composition are initiated that change postnatally to meet physiological demand. To examine the role of the protein phosphatase calcineurin in the initiation and maintenance of muscle fiber types, we used a "Flox-ON" approach to obtain muscle-specific overexpression of the modulatory calcineurin-interacting protein 1 (MCIP1/DSCR1), an inhibitor of calcineurin. Myo-Cre transgenic mice with early skeletal muscle-specific expression of Cre recombinase were used to activate the Flox-MCIP1 transgene. Contractile components unique to type 1 slow fibers were absent from skeletal muscle of adult Myo-Cre/Flox-MCIP1 mice, whereas oxidative capacity, myoglobin content, and mitochondrial abundance were unaltered. The soleus muscles of Myo-Cre/Flox-MCIP1 mice fatigued more rapidly than the wild type as a consequence of the replacement of the slow myosin heavy chain MyHC-1 with a fast isoform, MyHC-2A. MyHC-1 expression in Myo-Cre/Flox-MCIP1 embryos and early neonates was normal. These results demonstrate that developmental patterning of slow fibers is independent of calcineurin, while the maintenance of the slow-fiber phenotype in the adult requires calcineurin activity.
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PMID:Calcineurin is necessary for the maintenance but not embryonic development of slow muscle fibers. 1602 98

To gain more insight into the mechanism of muscle plasticity in response to mechanical overload, we analyzed the effects of bite -opening (BO, 3 mm increase in the vertical dimension for 2 weeks) and/or a calcineurin (CaN) inhibitor, cyclosporin A (CsA, 10 mg/kg body weight, once daily for 2 weeks, ip) treatment on the myosin heavy chain (MHC I, IIa, IId/x, IIb) mRNA levels, using real-time RT-PCR with specific primers and on the muscle mass in rat masseter. As compared with normal control (n = 6), the BO treatment (n = 6) significantly increased the MHC I (p < 0.05) and the IIa mRNA levels (p < 0.01), and the CsA treatment (n = 6) significantly decreased the MHC I mRNA level (p < 0.01) in association with the significant decrease in the MHC IIb mRNA level (p < 0.05). The BO + CsA treatment (n = 6) significantly increased the MHC IIa mRNA level (p < 0.01) in association with the significant decrease in the MHC IIb mRNA level (p < 0.01), as compared with control. The masseter muscle mass was significantly decreased by either the CsA (p < 0.05) or the BO + CsA treatment (p < 0.001), but slightly increased by the BO treatment. These results suggest that in rat masseter the BO treatment produces not only the up-regulation of MHC IIa mRNA independently of CaN-signaling pathways, but also the MHC mRNA transition from IIa to I and the muscle mass maintenance mainly of type IIb fiber through the CaN-signaling pathways.
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PMID:Effects of bite-opening and cyclosporin A on the mRNA levels of myosin heavy chain and the muscle mass in rat masseter. 1608 Aug

Mutations in the Drosophila calcineurin B2 gene cause the collapse of indirect flight muscles during mid stages of pupal development. Examination of cell fate-specific markers indicates that unlike mutations in genes such as vestigial, calcineurin B2 does not cause a shift in cell fate from indirect flight muscle to direct flight muscle. Genetic and molecular analyses indicate a severe reduction of myosin heavy chain gene expression in calcineurin B2 mutants, which accounts at least in part for the muscle collapse. Myofibrils in calcineurin B2 mutants display a variety of phenotypes, ranging from normal to a lack of sarcomeric structure. Calcineurin B2 also plays a role in the transition to an adult-specific isoform of troponin I during the late pupal stages, although the incompleteness of this transition in calcineurin B2 mutants does not contribute to the phenotype of muscle collapse. Together, these findings suggest a molecular basis for the indirect flight muscle hypercontractility phenotype observed in flies mutant for Drosophila calcineurin B2.
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PMID:Calcineurin function is required for myofilament formation and troponin I isoform transition in Drosophila indirect flight muscle. 1629 4

In vitro studies have used protein markers to distinguish between myogenic cells isolated from fast and slow skeletal muscles. The protein markers provide some support for the hypothesis that satellite cells from fast and slow muscles are different, but the data are equivocal. To test this hypothesis directly, three-dimensional skeletal muscle constructs were engineered from myogenic cells isolated from fast tibialis anterior (TA) and slow soleus (SOL) muscles of rats and functionality was tested. Time to peak twitch tension (TPT) and half relaxation time (RT(1/2)) were approximately 30% slower in constructs from the SOL. The slower contraction and relaxation times for the SOL constructs resulted in left shift of the force-frequency curve compared with those from the TA. Western blot analysis showed a 60% greater quantity of fast myosin heavy chain in the TA constructs. 14 days of chronic low-frequency electrical stimulation resulted in a 15% slower TPT and a 14% slower RT(1/2), but no change in absolute force production in the TA constructs. In SOL constructs, slow electrical stimulation resulted in an 80% increase in absolute force production with no change in TPT or RT(1/2). The addition of cyclosporine A did not prevent the increase in force in SOL constructs after chronic low-frequency electrical stimulation, suggesting that calcineurin is not responsible for the increase in force. We conclude that myogenic cells associated with a slow muscle are imprinted to produce muscle that contracts and relaxes slowly and that calcineurin activity cannot explain the response to a slow pattern of electrical stimulation.
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PMID:Cultured slow vs. fast skeletal muscle cells differ in physiology and responsiveness to stimulation. 1643 74


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