Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression

Skeletal muscle atrophy is a debilitating response to starvation and many systemic diseases including diabetes, cancer, and renal failure. We had proposed that a common set of transcriptional adaptations underlie the loss of muscle mass in these different states. To test this hypothesis, we used cDNA microarrays to compare the changes in content of specific mRNAs in muscles atrophying from different causes. We compared muscles from fasted mice, from rats with cancer cachexia, streptozotocin‐induced diabetes mellitus, uremia induced by subtotal nephrectomy, and from pair‐fed control rats. Although the content of >90% of mRNAs did not change, including those for the myofibrillar apparatus, we found a common set of genes (termed atrogins) that were induced or suppressed in muscles in these four catabolic states. Among the strongly induced genes were many involved in protein degradation, including polyubiquitins, Ub fusion proteins, the Ub ligases atrogin‐1/MAFbx and MuRF‐1, multiple but not all subunits of the 20S proteasome and its 19S regulator, and cathepsin L. Many genes required for ATP production and late steps in glycolysis were down‐regulated, as were many transcripts for extracellular matrix proteins. Some genes not previously implicated in muscle atrophy were dramatically up‐regulated (lipin, metallothionein, AMP deaminase, RNA helicase‐related protein, TG interacting factor) and several growth‐related mRNAs were down‐regulated (P311, JUN, IGF‐1‐BP5). Thus, different types of muscle atrophy share a common transcriptional program that is activated in many systemic diseases.—Lecker, S. H., Jagoe, R. T., Gilbert, A., Gomes, M., Baracos, V., Bailey, J., Price, S. R., Mitch, W. E., Goldberg, A. L. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression.—Stewart H. Lecker, R. Thomas Jagoe, Alexander Gilbert, Marcelo Gomes, Vickie Baracos, James Bailey, S. Russ Price, William E. Mitch, Alfred L. Goldberg Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 18, 39–51 (2004)

[1]  Keiji Tanaka,et al.  Expression of subunits of the 19S complex and of the PA28 activator in rat skeletal muscle , 1997, Molecular Biology Reports.

[2]  A. Goldberg,et al.  TNF‐α increases ubiquitin‐conjugating activity in skeletal muscle by up‐regulating UbcH2/E220k , 2003 .

[3]  P. Hasselgren,et al.  Sepsis upregulates the gene expression of multiple ubiquitin ligases in skeletal muscle. , 2003, The international journal of biochemistry & cell biology.

[4]  R. Paules,et al.  An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. , 2003, Molecular cell.

[5]  D. Glass.  Signalling pathways that mediate skeletal muscle hypertrophy and atrophy , 2003, Nature Cell Biology.

[6]  E. Carmeli,et al.  Expression of matrix metalloproteinases, inhibitor, and acid phosphatase in muscles of immobilized hindlimbs of rats , 2003, Muscle & nerve.

[7]  A. Goldberg,et al.  TNF-alpha increases ubiquitin-conjugating activity in skeletal muscle by up-regulating UbcH2/E220k. , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  A. Goldberg,et al.  Patterns of gene expression in atrophying skeletal muscles: response to food deprivation , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  G. Taylor,et al.  P311 induces a TGF-beta1-independent, nonfibrogenic myofibroblast phenotype. , 2002, The Journal of clinical investigation.

[10]  K. Webster,et al.  Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Accili,et al.  Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1 , 2002, Nature Genetics.

[12]  S. Wing,et al.  Ubiquitin-conjugating enzyme E214k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice. , 2002, American journal of physiology. Endocrinology and metabolism.

[13]  H. Stein,et al.  Aberrantly expressed c‐Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF‐κB , 2002, The EMBO journal.

[14]  C. Kahn,et al.  Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Rechsteiner,et al.  PA200, a nuclear proteasome activator involved in DNA repair , 2002, The EMBO journal.

[16]  Y. Toda,et al.  Identification of a novel smooth muscle associated protein, smap2, upregulated during neointima formation in a rat carotid endarterectomy model. , 2002, Biochimica et biophysica acta.

[17]  W. Mitch,et al.  Ubiquitin (UbC) Expression in Muscle Cells Is Increased by Glucocorticoids through a Mechanism Involving Sp1 and MEK1* , 2002, The Journal of Biological Chemistry.

[18]  V. Baracos.  Hypercatabolism and hypermetabolism in wasting states , 2002, Current opinion in clinical nutrition and metabolic care.

[19]  A. Hoeflich,et al.  IGF-binding protein-5: flexible player in the IGF system and effector on its own. , 2002, The Journal of endocrinology.

[20]  P. Hasselgren,et al.  C/EBP DNA-binding activity is upregulated by a glucocorticoid-dependent mechanism in septic muscle. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[21]  J. Lawrence,et al.  Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. Watt,et al.  The effect of galectin-1 on the differentiation of fibroblasts and myoblasts in vitro. , 2002, Journal of cell science.

[23]  A. Varshavsky,et al.  Construction and Analysis of Mouse Strains Lacking the Ubiquitin Ligase UBR1 (E3α) of the N-End Rule Pathway , 2001, Molecular and Cellular Biology.

[24]  A. Goldberg,et al.  Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  D. Attaix,et al.  Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting. , 2001, The Biochemical journal.

[26]  C. Rommel,et al.  Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways , 2001, Nature Cell Biology.

[27]  G. Yancopoulos,et al.  Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo , 2001, Nature Cell Biology.

[28]  D J Glass,et al.  Identification of Ubiquitin Ligases Required for Skeletal Muscle Atrophy , 2001, Science.

[29]  H. Ploegh,et al.  A novel active site‐directed probe specific for deubiquitylating enzymes reveals proteasome association of USP14 , 2001, The EMBO journal.

[30]  W. Souba,et al.  Glutamine metabolism in sepsis and infection. , 2001, The Journal of nutrition.

[31]  B. Bode.  Recent molecular advances in mammalian glutamine transport. , 2001, The Journal of nutrition.

[32]  K. Nakayama,et al.  U Box Proteins as a New Family of Ubiquitin-Protein Ligases* , 2001, The Journal of Biological Chemistry.

[33]  C. Beaudry,et al.  Identification and validation of P311 as a glioblastoma invasion gene using laser capture microdissection. , 2001, Cancer research.

[34]  A. Goldberg,et al.  What do we really know about the ubiquitin-proteasome pathway in muscle atrophy? , 2001, Current opinion in clinical nutrition and metabolic care.

[35]  Y. Kan,et al.  An important function of Nrf2 in combating oxidative stress: Detoxification of acetaminophen , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[36]  C. Auffray,et al.  Identification of altered gene expression in skeletal muscles from Duchenne muscular dystrophy patients , 2001, Neuromuscular Disorders.

[37]  Yi-Ping Li,et al.  Cytokines and oxidative signalling in skeletal muscle. , 2001, Acta physiologica Scandinavica.

[38]  Ping Xu,et al.  Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin , 2001, Nature Genetics.

[39]  V. Baracos,et al.  Coordinate expression of matrix-degrading proteinases and their activators and inhibitors in bovine skeletal muscle. , 2001, Journal of animal science.

[40]  J. Léger,et al.  Analysis of altered gene expression in rat soleus muscle atrophied by disuse , 2001, Journal of cellular biochemistry.

[41]  P. Singal,et al.  Metallothioneins, oxidative stress and the cardiovascular system. , 2000, Toxicology.

[42]  Yudong D. He,et al.  Functional Discovery via a Compendium of Expression Profiles , 2000, Cell.

[43]  J. Zierath,et al.  Insulin action and insulin resistance in human skeletal muscle , 2000, Diabetologia.

[44]  S. Bayol,et al.  Phenotypic expression of IGF binding protein transcripts in muscle, in vitro and in vivo. , 2000, Biochemical and biophysical research communications.

[45]  C. Farquharson,et al.  Identification of a family of noncanonical ubiquitin-conjugating enzymes structurally related to yeast UBC6. , 2000, Biochemical and biophysical research communications.

[46]  T. Pritts,et al.  The gene expression of ubiquitin ligase E3alpha is upregulated in skeletal muscle during sepsis in rats-potential role of glucocorticoids. , 2000, Biochemical and biophysical research communications.

[47]  D. Chrysis,et al.  Regulation of components of the ubiquitin system by insulin-like growth factor I and growth hormone in skeletal muscle of rats made catabolic with dexamethasone. , 1999, Endocrinology.

[48]  S. R. Datta,et al.  Cellular survival: a play in three Akts. , 1999, Genes & development.

[49]  A. Goldberg,et al.  Ubiquitin conjugation by the N-end rule pathway and mRNAs for its components increase in muscles of diabetic rats. , 1999, The Journal of clinical investigation.

[50]  B. Schoser,et al.  Matrix metalloproteinases MMP-2, MMP-7 and MMP-9 in denervated human muscle. , 1999, Neuroreport.

[51]  A. Musarò,et al.  IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1 , 1999, Nature.

[52]  Qiang Zhou,et al.  Cypher, a Striated Muscle-restricted PDZ and LIM Domain-containing Protein, Binds to α-Actinin-2 and Protein Kinase C* , 1999, The Journal of Biological Chemistry.

[53]  D. Torrents,et al.  Identification of a Membrane Protein, LAT-2, That Co-expresses with 4F2 Heavy Chain, an L-type Amino Acid Transport Activity with Broad Specificity for Small and Large Zwitterionic Amino Acids* , 1999, The Journal of Biological Chemistry.

[54]  P. Hasselgren.  Glucocorticoids and muscle catabolism. , 1999, Current opinion in clinical nutrition and metabolic care.

[55]  Claudine Jurkovitz,et al.  Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting. , 1999, American journal of physiology. Cell physiology.

[56]  H. Feldmann,et al.  Rpn4p acts as a transcription factor by binding to PACE, a nonamer box found upstream of 26S proteasomal and other genes in yeast , 1999, FEBS letters.

[57]  R. Bucala,et al.  An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[58]  W. Souba,et al.  Identification of glucocorticoid-responsive elements that control transcription of rat glutamine synthetase. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[59]  M. Toner,et al.  Posttranslational modifications of cardiac and skeletal muscle proteins by reactive oxygen species after burn injury in the rat. , 1999, Annals of surgery.

[60]  A. Goldberg,et al.  Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. , 1999, The Journal of nutrition.

[61]  A. Goldberg,et al.  Rates of ubiquitin conjugation increase when muscles atrophy, largely through activation of the N-end rule pathway. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[62]  K. Sakamaki,et al.  Purification, Molecular Cloning, and Characterization of TRP32, a Novel Thioredoxin-related Mammalian Protein of 32 kDa* , 1998, The Journal of Biological Chemistry.

[63]  R. Palmiter,et al.  A pair of adjacent glucocorticoid response elements regulate expression of two mouse metallothionein genes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[64]  D. Garrel,et al.  Activation of the ubiquitin pathway in rat skeletal muscle by catabolic doses of glucocorticoids. , 1997, The American journal of physiology.

[65]  T. Meyer,et al.  Sepsis is associated with increased mRNAs of the ubiquitin-proteasome proteolytic pathway in human skeletal muscle. , 1997, The Journal of clinical investigation.

[66]  A. Goldberg,et al.  Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. , 1996, The New England journal of medicine.

[67]  L. Phillips,et al.  Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-proteasome proteolytic pathway by a mechanism including gene transcription. , 1996, The Journal of clinical investigation.

[68]  C. Guézennec,et al.  Coordinate activation of lysosomal, Ca 2+-activated and ATP-ubiquitin-dependent proteinases in the unweighted rat soleus muscle. , 1996, The Biochemical journal.

[69]  B. Beaufrère,et al.  Increased mRNA levels for components of the lysosomal, Ca2+-activated, and ATP-ubiquitin-dependent proteolytic pathways in skeletal muscle from head trauma patients. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[70]  D. Breuillé,et al.  Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+ -activated, and ubiquitin-proteasome proteolytic pathways. , 1996, The Journal of clinical investigation.

[71]  W. Mitch,et al.  The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway. , 1996, The Journal of clinical investigation.

[72]  J. Wang,et al.  Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids. , 1996, The Journal of clinical investigation.

[73]  E. Bertolino,et al.  A Novel Homeobox Protein Which Recognizes a TGT Core and Functionally Interferes with a Retinoid-responsive Motif (*) , 1995, The Journal of Biological Chemistry.

[74]  A. Goldberg,et al.  Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma. , 1995, The American journal of physiology.

[75]  A. Goldberg,et al.  Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy. , 1995, The Biochemical journal.

[76]  D. Guardavaccaro,et al.  Inhibition of differentiation in myoblasts deprived of the interferon-related protein PC4. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[77]  J. Estrela,et al.  Increased ATP-ubiquitin-dependent proteolysis in skeletal muscles of tumor-bearing rats. , 1994, Cancer research.

[78]  J. M. Boyd,et al.  Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins , 1994, Cell.

[79]  W. Mitch,et al.  Acidosis and glucocorticoids concomitantly increase ubiquitin and proteasome subunit mRNAs in rat muscle. , 1994, The American journal of physiology.

[80]  I. Ferrer,et al.  Parvalbumin immunohistochemistry in denervated skeletal muscle , 1994, Neuropathology and applied neurobiology.

[81]  S. Wing,et al.  14-kDa ubiquitin-conjugating enzyme: structure of the rat gene and regulation upon fasting and by insulin. , 1994, The American journal of physiology.

[82]  A. Goldberg,et al.  Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes. , 1994, The Journal of clinical investigation.

[83]  N. Agell,et al.  Ubiquitin gene expression is increased in skeletal muscle of tumour‐bearing rats , 1994, FEBS letters.

[84]  J. M. Boyd,et al.  Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. , 1994, Cell.

[85]  S. Kira,et al.  Cathepsin L activity is increased in alveolar macrophages and bronchoalveolar lavage fluid of smokers. , 1993, The American review of respiratory disease.

[86]  A. Goldberg,et al.  Glucocorticoids activate the ATP-ubiquitin-dependent proteolytic system in skeletal muscle during fasting. , 1993, The American journal of physiology.

[87]  Alexander Varshavsky,et al.  The tails of ubiquitin precursors are ribosomal proteins whose fusion to ubiquitin facilitates ribosome biogenesis , 1989, Nature.

[88]  A. Kayali,et al.  Sensitivity of myofibrillar proteins to glucocorticoid-induced muscle proteolysis. , 1987, The American journal of physiology.

[89]  J. Lowenstein,et al.  The purine nucleotide cycle in skeletal muscle. , 1978, Federation proceedings.