Localization and Regulation of the N Terminal Splice Variant of PGC-1αin Adult Skeletal Muscle Fibers

The transcriptional coactivator peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α) regulates expression of genes for metabolism and muscle fiber type. Recently, a novel splice variant of PGC-1α(NT-PGC-1α, amino acids 1–270) was cloned and found to be expressed in muscle. Here we use Flag-tagged NT-PGC-1αto examine the subcellular localization and regulation of NT-PGC-1αin skeletal muscle fibers. Flag-NT-PGC-1αis located predominantly in the myoplasm. Nuclear NT-PGC-1αcan be increased by activation of protein kinase A. Activation of p38 MAPK by muscle activity or of AMPK had no effect on the subcellular distribution of NT-PGC-1α. Inhibition of CRM1-mediated export only caused relatively slow nuclear accumulation of NT-PGC-1α, indicating that nuclear export of NT-PGC-1αmay be mediated by both CRM1-dependent and -independent pathways. Together these results suggest that the regulation of NT-PGC-1αin muscle fibers may be very different from that of the full-length PGC-1α, which is exclusively nuclear.

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Activity- and Calcineurin-independent Nuclear Shuttling of NFATc1, but Not NFATc3, in Adult Skeletal Muscle Fibers

Molecular Biology of the Cell ◽

10.1091/mbc.e05-08-0780 ◽

2006 ◽

Vol 17 (4) ◽

pp. 1570-1582 ◽

Cited By ~ 30

Author(s):

Tiansheng Shen ◽

Yewei Liu ◽

Zoltán Cseresnyés ◽

Arie Hawkins ◽

William R. Randall ◽

...

Keyword(s):

Skeletal Muscle ◽

Electrical Stimulation ◽

Nuclear Export ◽

Muscle Fibers ◽

Nuclear Accumulation ◽

Leptomycin B ◽

Adult Skeletal Muscle ◽

Casein Kinase 1 ◽

Nuclear Uptake ◽

Skeletal Muscle Fibers

The transcription factor NFATc1 may be involved in slow skeletal muscle gene expression. NFATc1 translocates from cytoplasm to nuclei during slow fiber type electrical stimulation of skeletal muscle fibers because of activation of the Ca2+-dependent phosphatase calcineurin, resulting in nuclear factor of activated T-cells (NFAT) dephosphorylation and consequent exposure of its nuclear localization signal. Here, we find that unstimulated adult skeletal muscle fibers exhibit a previously unanticipated nucleocytoplasmic shuttling of NFATc1 without appreciable nuclear accumulation. In resting fibers, the nuclear export inhibitor leptomycin B caused nuclear accumulation of NFATc1 (but not of isoform NFATc3) and formation of NFATc1 intranuclear bodies independent of calcineurin. The rate of nuclear uptake of NFATc1 was 4.6 times lower in resting fibers exposed to leptomycin B than during electrical stimulation. Inhibitors of glycogen synthase kinase and protein kinase A or of casein kinase 1 slowed the decay of nuclear NFATc1 after electrical stimulation, but they did not cause NFATc1 nuclear uptake in unstimulated fibers. We propose that two nuclear translocation pathways, one pathway mediated by calcineurin activation and NFAT dephosphorylation and the other pathway independent of calcineurin and possibly independent of NFAT dephosphorylation, determine the distribution of NFATc1 between cytoplasm and nuclei in adult skeletal muscle.

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Kinetics of nuclear-cytoplasmic translocation of Foxo1 and Foxo3A in adult skeletal muscle fibers

AJP Cell Physiology ◽

10.1152/ajpcell.00027.2012 ◽

2012 ◽

Vol 303 (9) ◽

pp. C977-C990 ◽

Cited By ~ 25

Author(s):

Tova Neustadt Schachter ◽

Tiansheng Shen ◽

Yewei Liu ◽

Martin F. Schneider

Keyword(s):

Skeletal Muscle ◽

Nuclear Export ◽

Time Course ◽

Chromosome Region ◽

Muscle Fibers ◽

High Rate ◽

Nuclear Accumulation ◽

Experimental Conditions ◽

Adult Skeletal Muscle ◽

Skeletal Muscle Fibers

In skeletal muscle, the transcription factors Foxo1 and Foxo3A control expression of proteins that mediate muscle atrophy, making the nuclear concentration and nuclear-cytoplasmic movements of Foxo1 and Foxo3A of therapeutic interest in conditions of muscle wasting. Here, we use Foxo-GFP fusion proteins adenovirally expressed in cultured adult mouse skeletal muscle fibers to characterize the time course of nuclear efflux of Foxo1-GFP in response to activation of the insulin-like growth factor-1 (IGF-1)/phosphatidylinositol-3-kinase (PI3K)/Akt pathway to determine the time course of nuclear influx of Foxo1-GFP during inhibition of this pathway and to show that Akt mediates the efflux of nuclear Foxo1-GFP induced by IGF-1. Localization of endogenous Foxo1 in muscle fibers, as determined via immunocytochemistry, is consistent with that of Foxo1-GFP. Inhibition of the nuclear export carrier chromosome region maintenance 1 by leptomycin B (LMB) traps Foxo1 in the nucleus and results in a relatively rapid rate of Foxo1 nuclear accumulation, consistent with a high rate of nuclear-cytoplasmic shuttling of Foxo1 under control conditions before LMB application, with near balance of unidirectional influx and efflux. Expressed Foxo3A-GFP shuttles ∼20-fold more slowly than Foxo1-GFP. Our approach allows quantitative kinetic characterization of Foxo1 and Foxo3A nuclear-cytoplasmic movements in living muscle fibers under various experimental conditions.

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Activity-dependent nuclear translocation and intranuclear distribution of NFATc in adult skeletal muscle fibers

The Journal of Cell Biology ◽

10.1083/jcb.200103020 ◽

2001 ◽

Vol 155 (1) ◽

pp. 27-40 ◽

Cited By ~ 130

Author(s):

Yewei Liu ◽

Zoltán Cseresnyés ◽

William R. Randall ◽

Martin F. Schneider

Keyword(s):

Skeletal Muscle ◽

Electrical Stimulation ◽

Nuclear Translocation ◽

Fiber Type ◽

Muscle Fibers ◽

Adult Skeletal Muscle ◽

Skeletal Muscle Fibers ◽

Slow Twitch ◽

Nuclear Foci ◽

Fast Twitch

TTranscription factor nuclear factor of activated T cells NFATc (NFATc1, NFAT2) may contribute to slow-twitch skeletal muscle fiber type–specific gene expression. Green fluorescence protein (GFP) or FLAG fusion proteins of either wild-type or constitutively active mutant NFATc [NFATc(S→A)] were expressed in cultured adult mouse skeletal muscle fibers from flexor digitorum brevis (predominantly fast-twitch). Unstimulated fibers expressing NFATc(S→A) exhibited a distinct intranuclear pattern of NFATc foci. In unstimulated fibers expressing NFATc–GFP, fluorescence was localized at the sarcomeric z-lines and absent from nuclei. Electrical stimulation using activity patterns typical of slow-twitch muscle, either continuously at 10 Hz or in 5-s trains at 10 Hz every 50 s, caused cyclosporin A–sensitive appearance of fluorescent foci of NFATc–GFP in all nuclei. Fluorescence of nuclear foci increased during the first hour of stimulation and then remained constant during a second hour of stimulation. Kinase inhibitors and ionomycin caused appearance of nuclear foci of NFATc–GFP without electrical stimulation. Nuclear translocation of NFATc–GFP did not occur with either continuous 1 Hz stimulation or with the fast-twitch fiber activity pattern of 0.1-s trains at 50 Hz every 50 s. The stimulation pattern–dependent nuclear translocation of NFATc demonstrated here could thus contribute to fast-twitch to slow-twitch fiber type transformation.

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Post-Tetanic Calcium Transients In Adult Skeletal Muscle Fibers Are Frequency-Dependent And Fiber Type Specific

Biophysical Journal ◽

10.1016/j.bpj.2008.12.953 ◽

2009 ◽

Vol 96 (3) ◽

pp. 11a

Author(s):

Mariana Casas ◽

Reinaldo Figueroa ◽

Isaac Garcia ◽

Enrique Jaimovich

Keyword(s):

Skeletal Muscle ◽

Fiber Type ◽

Muscle Fibers ◽

Calcium Transients ◽

Frequency Dependent ◽

Adult Skeletal Muscle ◽

Skeletal Muscle Fibers

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PO-009 Exercise Adaptation of Skeletal Muscle Fibers: The Role of MicroRNAs

Exercise Biochemistry Review ◽

10.14428/ebr.v1i3.8963 ◽

2018 ◽

Vol 1 (3) ◽

Author(s):

Jian Shou ◽

Peijie Chen ◽

Weihua Xiao

Keyword(s):

Skeletal Muscle ◽

Endurance Training ◽

Fiber Type ◽

Muscle Fibers ◽

Mammalian Target Of Rapamycin ◽

Peroxisome Proliferator ◽

Oxidative Potential ◽

Ribosomal Protein S6 ◽

Skeletal Muscle Fibers ◽

Exercise Adaptation

Objective Explore the relationship between exercise adaptation of skeletal muscle fibers and microRNAs. Methods Research related papers. Results endurance training can switch muscle fiber type by promoting microRNAs (miR-208b, miR-499). For example, the conversion from fast Type IIb muscle fibers to slower Type IIx/d muscle fibers, or from Type IIx muscle fibers to Type IIa muscle fibers. Endurance training can also promote the expression of Peroxisome Proliferator Receptor Gamma Coactivator-1α (PGC-1α) and enhance the oxidative potential for slow muscle fibers by inhibiting some microRNAs such as miR-23a. Resistance training can activate insulin-like growth factor-1/phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin/P70 ribosomal protein S6 kinase (IGF-1/PI3K/Akt/mTOR/P70S6K) pathways and promote fast muscle fibers hypertrophy by inhibiting negative microRNAs (miR-1,miR-133,miR-128a) and promoting positive microRNAs (miR-27,miR-29,miR-486). Conclusions MicroRNAs play an important role in the exercise adaptation of skeletal muscle fibers.

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Agonists of the Peroxisome Proliferator–Activated Receptor Alpha Induce a Fiber-Type–Selective Transcriptional Response in Rat Skeletal Muscle

Toxicological Sciences ◽

10.1093/toxsci/kfl019 ◽

2006 ◽

Vol 92 (2) ◽

pp. 578-586 ◽

Cited By ~ 32

Author(s):

Angus T. De Souza ◽

Paul D. Cornwell ◽

Xudong Dai ◽

Michelle J. Caguyong ◽

Roger G. Ulrich

Keyword(s):

Skeletal Muscle ◽

Fiber Type ◽

Transcriptional Response ◽

Peroxisome Proliferator ◽

Rat Skeletal Muscle ◽

Peroxisome Proliferator Activated Receptor ◽

Receptor Alpha

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The Adaptive Potential of Skeletal Muscle Fibers

Canadian Journal of Applied Physiology ◽

10.1139/h02-023 ◽

2002 ◽

Vol 27 (4) ◽

pp. 423-448 ◽

Cited By ~ 109

Author(s):

Dirk Pette

Keyword(s):

Skeletal Muscle ◽

Fiber Type ◽

Muscle Fibers ◽

Protein Isoforms ◽

Mammalian Skeletal Muscle ◽

Adaptive Potential ◽

Hybrid Fibers ◽

Neuromuscular Activity ◽

Skeletal Muscle Fibers ◽

Initial Location

Mammalian skeletal muscle fibers display a great adaptive potential. This potential results from the ability of muscle fibers to adjust their molecular, functional, and metabolic properties in response to altered functional demands, such as changes in neuromuscular activity or mechanical loading. Adaptive changes in the expression of myofibrillar and other protein isoforms result in fiber type transitions. These transitions occur in a sequential order and encompass a spectrum of pure and hybrid fibers. Depending on the quality, intensity, and duration of the alterations in functional demand, muscle fibers may undergo functional transitions in the direction of slow or fast, as well as metabolic transitions in the direction of aerobic-oxidative or glycotytic. The maximum range of possible transitions in either direction depends on the fiber phenotype and is determined by its initial location in the fiber spectrum. Key words: Ca-sequestering proteins, energy metabolism, fiber type transition, myofibrillar protein isofonns, myosin, neuromuscular activity

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Phenotypic Modulation of Skeletal Muscle Fibers in LPIN1-Deficient Lipodystrophic (fld) Mice

Veterinary Pathology ◽

10.1177/0300985818809126 ◽

2018 ◽

Vol 56 (2) ◽

pp. 322-331

Author(s):

Rani S. Sellers ◽

S. Radma Mahmood ◽

Geoffrey S. Perumal ◽

Frank P. Macaluso ◽

Irwin J. Kurland

Keyword(s):

Electron Microscopy ◽

Skeletal Muscle ◽

Fiber Type ◽

Periodic Acid ◽

Muscle Fibers ◽

Myosin Atpase ◽

Hybrid Fibers ◽

Periodic Acid Schiff ◽

Skeletal Muscle Fibers ◽

Lipin 1

Lipin-1 ( Lpin1)–deficient lipodystrophic mice have scant and immature adipocytes and develop transient fatty liver early in life. Unlike normal mice, these mice cannot rely on stored triglycerides to generate adenosine triphosphate (ATP) from the β-oxidation of fatty acids during periods of fasting. To compensate, these mice store much higher amounts of glycogen in skeletal muscle and liver than wild-type mice in order to support energy needs during periods of fasting. Our studies demonstrated that there are phenotypic changes in skeletal muscle fibers that reflect an adaptation to this unique metabolic situation. The phenotype of skeletal muscle (soleus, gastrocnemius, plantaris, and extensor digitorum longus [EDL]) from Lpin1-/- was evaluated using various methods including immunohistochemistry for myosin heavy chains (Myh) 1, 2, 2a, 2b, and 2x; enzyme histochemistry for myosin ATPase, cytochrome-c oxidase (COX), and succinyl dehydrogenase (SDH); periodic acid–Schiff; and transmission electron microscopy. Fiber-type changes in the soleus muscle of Lpin1-/- mice were prominent and included decreased Myh1 expression with concomitant increases in Myh2 expression and myosin-ATPase activity; this change was associated with an increase in the presence of Myh1/2a or Myh1/2x hybrid fibers. Alterations in mitochondrial enzyme activity (COX and SDH) were apparent in the myofibers in the soleus, gastrocnemius, plantaris, and EDL muscles. Electron microscopy revealed increases in the subsarcolemmal mitochondrial mass in the muscles of Lpin1-/- mice. These data demonstrate that lipin-1 deficiency results in phenotypic fiber-specific modulation of skeletal muscle necessary for compensatory fuel utilization adaptations in lipodystrophy.

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