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.Adult mammalian skeletal muscle is composed of multinucleated myofibers that can be classified based upon expression of one of four adult myosin heavy chain (MyHC) genes that contribute specific contractile properties (23). Muscle fiber types are identified as either type 1 (slow) or type 2 (fast) based upon velocity of contraction and rate of fatigue. Type 1 slow fibers express MyHC-1, are highly oxidative, and are rich in both mitochondria and myoglobin, which gives them their red color. Type 2 fast fibers can be further subdivided as 2A, 2X (also denoted 2D), and 2B based upon expression of MyHC-2A, MyHC-2X, and MyHC-2B, respectively. Type 2A fibers are oxidative and are rich in both mitochondria and myoglobin. In contrast, type 2B fibers are glycolytic and lack myoglobin. Type 2X fibers have an intermediate phenotype. In the mouse embryo, a pattern of fast and slow muscle fibers is established during several waves of myoblast fusion. Primary myofibers are formed during embryonic day 12 (E12) to E14 (18). A second wave of myotube formation occurs during E16 to E18. MyHC-1 is expressed both in the embryo and adult, whereas embryo-specific fast fiber isoforms, MyHC-emb and MyHCneo, are replaced by adult isoforms after birth.Postnatally, skeletal fiber-type composition is highly plastic and remodels in response to neuronal input and motor function in order to meet physiological demand (26). For instance, inactivity results in a general shift in MyHC expression and metabolic properties along the progression of 132A3 2X32B. Endurance training promotes a shift in the opposite direction, 2B32X32A31 (28). The calcium-activated protein phosphatase calcineurin has been proposed as an important regulator of muscle fiber type that activates the transcription f...
Rationale: Despite overwhelming evidence of the importance of circadian rhythms in cardiovascular health and disease, little is known regarding the circadian regulation of intracellular signaling pathways controlling cardiac function and remodeling.Objective: To assess circadian changes in processes dependent on the protein phosphatase calcineurin, relative to changes in phosphorylation of cardiac proteins, in normal, hypertrophic, and failing hearts. Methods and Results:We found evidence of large circadian oscillations in calcineurin-dependent activities in the left ventricle of healthy C57BL/6 mice. Calcineurin-dependent transcript levels and nuclear occupancy of the NFAT (nuclear factor of activated T cells) regularly fluctuated as much as 20-fold over the course of a day, peaking in the morning when mice enter a period of rest. Phosphorylation of the protein phosphatase 1 inhibitor 1 (I-1), a direct calcineurin substrate, and phospholamban, an indirect target, oscillated directly out of phase with calcineurin-dependent signaling. Using a surgical model of cardiac pressure overload, we found that although calcineurin-dependent activities were markedly elevated, the circadian pattern of activation was maintained, whereas, oscillations in phospholamban and I-1 phosphorylation were lost. Changes in the expression of fetal gene markers of heart failure did not mirror the rhythm in calcineurin/NFAT activation, suggesting that these may not be direct transcriptional target genes. Cardiac function in mice subjected to pressure overload was significantly lower in the morning than in the evening when assessed by echocardiography. Key Words: calcineurin Ⅲ circadian rhythms Ⅲ heart failure Ⅲ RCAN1/MCIP1 C ircadian rhythms are self-sustaining, 24-hour cycles in molecular, biochemical, and behavioral parameters that help an organism prepare for anticipated changes in physiological demand. Many important cardiovascular factors, including metabolism, heart rate, blood pressure, and hormone release, oscillate over a 24-hour period. 1 In humans, the incidence of adverse cardiac events, such as myocardial infarction, ventricular tachycardia, and death from ischemic heart disease, vary according to the time of day. 2 Despite overwhelming evidence of the importance of circadian rhythms in cardiovascular health and disease, little is known regarding the circadian regulation of intracellular signaling pathways in the heart. The molecular basis of the circadian clock consists of cellautonomous, positive and negative transcriptional and posttranscriptional feedback loops. 3 The "master clock," located in the suprachiasmatic nucleus within the hypothalamus, influences the phase of independent molecular clocks found in peripheral organs, including the heart. Many cells and tissues also display circadian fluctuations in cytoplasmic Ca 2ϩ levels, although the source of these Ca 2ϩ oscillations and their relationship to the transcriptional clock mechanism is not fully understood. 4 Dysregulation of Ca 2ϩ handling is a hallmark of hear...
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