Chapter ten - Regulation of Nucleocytoplasmic Transport in Skeletal Muscle

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Abstract

Proper skeletal muscle function is dependent on spatial and temporal control of gene expression in multinucleated myofibers. In addition, satellite cells, which are tissue-specific stem cells that contribute critically to repair and maintenance of skeletal muscle, are also required for normal muscle physiology. Gene expression in both myofibers and satellite cells is dependent upon nuclear proteins that require facilitated nuclear transport. A unique challenge for myofibers is controlling the transcriptional activity of hundreds of nuclei in a common cytoplasm yet achieving nuclear selectivity in transcription at specific locations such as neuromuscular synapses and myotendinous junctions. Nucleocytoplasmic transport of macromolecular cargoes is regulated by a complex interplay among various components of the nuclear transport machinery, namely nuclear pore complexes, nuclear envelope proteins, and various soluble transport receptors. The focus of this review is to highlight what is known about the nuclear transport machinery and its regulation in skeletal muscle and to consider the unique challenges that multinucleated muscle cells as well as satellite cells encounter in regulating nucleocytoplasmic transport during cell differentiation and tissue adaptation. Understanding how regulated nucleocytoplasmic transport controls gene expression in skeletal muscle may lead to further insights into the mechanisms contributing to muscle growth and maintenance throughout the lifespan of an individual.

Introduction

Skeletal muscle is a very plastic tissue that readily undergoes changes in mass and function in response to aging, injury, and disease. Such changes in muscle can impact breathing, locomotion, and metabolism and affect motility and lifespan. Proper skeletal muscle function is dependent on spatial and temporal control of gene expression mediated by proteins, such as transcription factors, that require facilitated transport to enter the nuclei. The subcellular localization of these regulatory proteins must be tightly controlled because altered import or export could result in aberrant muscle function.

Proper muscle function is dependent on myofibers, which are multinucleated cells containing many hundreds of nuclei distributed along the length of the cell in a common cytoplasm. Alongside each myofiber are adult muscle stem cells, called satellite cells, that lay beneath the basal lamina surrounding each myofiber. These satellite cells are normally quiescent but in response to muscle damage they are activated to begin proliferating and undergo differentiation and eventual fusion with each other or existing myofibers to repair muscles in a process called myogenesis. Myogenesis can be modeled in vitro by culturing myoblasts, the progeny of satellite cells, and inducing them to differentiate into multinucleated myotubes by changes in culture media. Myogenesis both in vivo and in vitro requires the coordinate activation and repression of many genes. Numerous nuclear proteins are required for proper gene expression and the nuclear repertoire of these proteins is very different along the myogenic continuum of quiescent satellite cells to mature postmitotic myofibers. How satellite cells differentially regulate nucleocytoplasmic transport of these nuclear proteins critical for regulating gene expression during quiescence, activation, and differentiation is unknown. In addition, how a myofiber with hundreds of nuclei coordinates and regulates nucleocytoplasmic transport is not clear.

Section snippets

Nuclear Envelope

The nuclear envelope of eukaryotic cells provides separation of the genetic material and transcriptional machinery within the nucleus from the translational machinery in the cytoplasm enhancing regulation of gene expression. The nuclear envelope is comprised of two lipid membrane bilayers, the outer nuclear membrane which is contiguous with the endoplasmic reticulum and the inner nuclear membrane which faces the nucleoplasm (Hetzer and Wente, 2009). The inner nuclear membrane contains integral

Nuclear Pore Complexes

The nuclear envelope is perforated by nuclear pore complexes (NPCs) which fuse the outer nuclear membrane and inner nuclear membrane together to create channels for nucleocytoplasmic transport (Fig. 10.1; Lim and Fahrenkrog, 2006). NPCs are multiprotein suprastructures (~ 50 MDa) which provide channels for the nucleocytoplasmic exchange of ions and macromolecules (Alber et al., 2007). While smaller ions and molecules can diffuse through the NPC, molecules larger than ~ 40 kDa require a targeting

Nuclear Import Pathways

Nuclear transport is a process whereby proteins or other macromolecules traverse the NPC either by directly interacting with peripheral FG-Nups within the NPC channel or by binding to import or export receptors that mediate transport through the NPC (Walde and Kehlenbach, 2010). The majority of nuclear transport receptors are karyopherin family members termed importins, transportins, or exportins which mediate transport across the NPC in an energy-dependent manner (Tran and Wente, 2006, Weis,

Identifying Classical Nuclear Import-Dependent Cargoes

Identifying the specific cargo proteins that are transported via various nucleocytoplasmic transport pathways is key for understanding the regulatory networks that govern cell function. Here we focus on how cNLS-dependent cargoes are identified since this pathway is the best characterized nuclear transport pathway; however, many of the challenges in cargo identification presented here apply also to other receptor-mediated transport pathways. In Mus musculus, 30–55% of nuclear proteins are

Remodeling of the Nuclear Transport Machinery

Alterations in global nucleocytoplasmic transport provide another layer of control over gene expression. Global changes in the efficiency or rate of nuclear transport can occur through alterations or remodeling of key components of the nuclear transport machinery. For example, altering the expression or localization of karyopherin transport receptors, Ran and/or Ran-associated proteins, or Nups results in changes in transport efficiency (Hodel et al., 2001, Hodel and Harreman, 2006; Riddick and

Challenges in Studying Nucleocytoplasmic Transport in Multinucleated Cells

The basic mechanics for nucleocytoplasmic transport of proteins and RNA identified to date and described in this review have almost exclusively been examined in cells with a single nucleus. Skeletal muscle is the only permanent multinucleated cell type in the body and constitutes ~ 50% of body mass; yet, how these cells spatially and temporally regulate and coordinate nucleocytoplasmic transport among hundreds of nuclei is unknown.

Spatial and temporal regulation of nucleocytoplasmic transport

Summary

Nucleocytoplasmic transport plays a key regulatory role in cellular physiology. While much is known about facilitated nuclear transport in other cell types, the study of nucleocytoplasmic transport in skeletal muscle is still in its infancy. Multinucleated myofibers are faced with unique challenges compared to most other mammalian cell types in controlling the function of hundreds of nuclei in a common cytoplasm. Although a fair bit is known about nuclear envelope proteins in skeletal muscle

Acknowledgments

G. K. P. is supported by National Institute of Health grants AR051372, AR052730, AR047314, and NS059340.

References (148)

  • R. Fagerlund et al.

    Arginine/lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin alpha 5

    J. Biol. Chem.

    (2002)
  • R.S. Faustino et al.

    Ceramide regulation of nuclear protein import

    J. Lipid Res.

    (2008)
  • J. Fernandez-Martinez et al.

    Nuclear pore complex biogenesis

    Curr. Opin. Cell Biol.

    (2009)
  • M.R. Fontes et al.

    Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-alpha

    J. Mol. Biol.

    (2000)
  • M.R. Fontes et al.

    Structural basis for the specificity of bipartite nuclear localization sequence binding by importin-alpha

    J. Biol. Chem.

    (2003)
  • D. Frenkiel-Krispin et al.

    Structural analysis of a metazoan nuclear pore complex reveals a fused concentric ring architecture

    J. Mol. Biol.

    (2010)
  • D.S. Goldfarb et al.

    Importin alpha: A multipurpose nuclear-transport receptor

    Trends Cell Biol.

    (2004)
  • M.W. Hetzer et al.

    Border control at the nucleus: Biogenesis and organization of the nuclear membrane and pore complexes

    Dev. Cell

    (2009)
  • M.R. Hodel et al.

    Dissection of a nuclear localization signal

    J. Biol. Chem.

    (2001)
  • A.E. Hodel et al.

    Nuclear localization signal receptor affinity correlates with in vivo localization in Saccharomyces cerevisiae

    J. Biol. Chem.

    (2006)
  • J.K. Hood et al.

    Cse1p is required for export of Srp1p/importin-alpha from the nucleus in Saccharomyces cerevisiae

    J. Biol. Chem.

    (1998)
  • J. Hu et al.

    Novel importin-alpha family member Kpna7 is required for normal fertility and fecundity in the mouse

    J. Biol. Chem.

    (2010)
  • M. Iwamoto et al.

    Two distinct repeat sequences of Nup98 nucleoporins characterize dual nuclei in the binucleated ciliate tetrahymena

    Curr. Biol.

    (2009)
  • D. Kalderon et al.

    A short amino acid sequence able to specify nuclear location

    Cell

    (1984)
  • J. Kind et al.

    Genome-nuclear lamina interactions and gene regulation

    Curr. Opin. Cell Biol.

    (2010)
  • M. Kodiha et al.

    Oxidative stress mislocalizes and retains transport factor importin-alpha and nucleoporins Nup153 and Nup88 in nuclei where they generate high molecular mass complexes

    Biochim. Biophys. Acta

    (2008)
  • M. Kohler et al.

    Cloning of two novel human importin-alpha subunits and analysis of the expression pattern of the importin-alpha protein family

    FEBS Lett.

    (1997)
  • U. Kutay et al.

    Leucine-rich nuclear-export signals: Born to be weak

    Trends Cell Biol.

    (2005)
  • U. Kutay et al.

    Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor

    Cell

    (1997)
  • A. Lange et al.

    Classical nuclear localization signals: Definition, function, and interaction with importin alpha

    J. Biol. Chem.

    (2007)
  • R.Y. Lim et al.

    The nuclear pore complex up close

    Curr. Opin. Cell Biol.

    (2006)
  • T.G. Lonhienne et al.

    Importin-beta is a GDP-to-GTP exchange factor of Ran: Implications for the mechanism of nuclear import

    J. Biol. Chem.

    (2009)
  • F. Lupu et al.

    Nuclear pore composition regulates neural stem/progenitor cell differentiation in the mouse embryo

    Dev. Cell

    (2008)
  • A. Mattout et al.

    Nuclear lamins, diseases and aging

    Curr. Opin. Cell Biol.

    (2006)
  • K.L. Abbott et al.

    Activation and cellular localization of the cyclosporine A-sensitive transcription factor NF-AT in skeletal muscle cells

    Mol. Biol. Cell

    (1998)
  • A. Ahluwalia et al.

    Impaired angiogenesis in aging myocardial microvascular endothelial cells is associated with reduced importin alpha and decreased nuclear transport of HIF1 alpha: Mechanistic implications

    J. Physiol. Pharmacol.

    (2010)
  • F. Alber et al.

    The molecular architecture of the nuclear pore complex

    Nature

    (2007)
  • J.N. Artaza et al.

    Endogenous expression and localization of myostatin and its relation to myosin heavy chain distribution in C2C12 skeletal muscle cells

    J. Cell. Physiol.

    (2002)
  • S.A. Berman et al.

    Localization of an acetylcholine receptor intron to the nuclear membrane

    Science

    (1990)
  • I.H. Chen et al.

    Nuclear envelope transmembrane proteins (NETs) that are up-regulated during myogenesis

    BMC Cell Biol.

    (2006)
  • Y.M. Chook et al.

    Nuclear import by karyopherin-betas: Recognition and inhibition

    Biochim. Biophysic. Acta

    (2010)
  • S. Clavel et al.

    Regulation of the intracellular localization of Foxo3a by stress-activated protein kinase signaling pathways in skeletal muscle cells

    Mol. Cell. Biol.

    (2010)
  • M. Cokol et al.

    Finding nuclear localization signals

    EMBO Rep.

    (2000)
  • A. Cook et al.

    Structural biology of nucleocytoplasmic transport

    Annu. Rev. Biochem.

    (2007)
  • R. Cortes et al.

    Influence of heart failure on nucleocytoplasmic transport in human cardiomyocytes

    Cardiovasc. Res.

    (2010)
  • N. Crampton et al.

    Oxidative stress inhibits nuclear protein export by multiple mechanisms that target FG nucleoporins and Crm1

    Mol. Biol. Cell

    (2009)
  • D.J. Dix et al.

    Myosin mRNA accumulation and myofibrillogenesis at the myotendinous junction of stretched muscle fibers

    J. Cell Biol.

    (1990)
  • C.M. Doucet et al.

    Nuclear pore biogenesis into an intact nuclear envelope

    Chromosoma

    (2010)
  • E.E. Dupont-Versteegden et al.

    Nuclear translocation of EndoG at the initiation of disuse muscle atrophy and apoptosis is specific to myonuclei

    Am. J. Physiol. Regul. Integr. Comp. Physiol.

    (2006)
  • C. Faul et al.

    Protein kinase A, Ca2+/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes

    Mol. Cell. Biol.

    (2007)
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