Skeletal muscle gene expression profiles in 20–29 year old and 65–71 year old women

Gene expression profiling may provide leads for investigations of the molecular basis of functional declines associated with aging. In this study, high-density oligonucleotide arrays were used to probe the patterns of gene expression in skeletal muscle of seven young women (20-29 years old) and eight healthy older women (65-71 years old). The older subjects had reduced muscle mass, strength, and peak oxygen consumption relative to young women. There were approximately 1000 probe sets that suggested differential gene expression in younger and older muscle according to statistical criteria. The most highly overexpressed genes (>3-fold) in older muscle were p21 (cyclin-dependent kinase inhibitor 1A), which might reflect increased DNA damage, perinatal myosin heavy chain, which might reflect increased muscle fiber regeneration, and tomoregulin, which does not have a defined function in muscle. More than 40 genes encoding proteins that bind to pre-mRNAs or mRNAs were expressed at higher levels in older muscle. More than 100 genes involved in energy metabolism were expressed at lower levels in older muscle. In general, these results support previous observations on the differences in gene expression profiles between younger and older men.

[1]  K. Yarasheski,et al.  Serum myostatin-immunoreactive protein is increased in 60-92 year old women and men with muscle wasting. , 2002, The journal of nutrition, health & aging.

[2]  Douglas L. Rothman,et al.  Mitochondrial Dysfunction in the Elderly: Possible Role in Insulin Resistance , 2003, Science.

[3]  G. Dreyfuss,et al.  Messenger-RNA-binding proteins and the messages they carry , 2002, Nature Reviews Molecular Cell Biology.

[4]  Stephen Welle,et al.  Gene expression profile of aging in human muscle. , 2003, Physiological genomics.

[5]  W. Frontera,et al.  Skeletal muscle fiber quality in older men and women. , 2000, American journal of physiology. Cell physiology.

[6]  Y. Abe,et al.  Identification of CGI-121, a novel PRPK (p53-related protein kinase)-binding protein. , 2003, Biochemical and biophysical research communications.

[7]  R M Enoka,et al.  Sex differences in the fatigability of arm muscles depends on absolute force during isometric contractions. , 2001, Journal of applied physiology.

[8]  S. R. Datta,et al.  DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein , 2002, Science.

[9]  Eric P. Hoffman,et al.  Expression Profiling in the Muscular Dystrophies Identification of Novel Aspects of Molecular Pathophysiology , 2000 .

[10]  R. Reddel,et al.  Hsp70 family member, mot-2/mthsp70/GRP75, binds to the cytoplasmic sequestration domain of the p53 protein. , 2002, Experimental cell research.

[11]  Andrew I. Brooks,et al.  Computational method for reducing variance with Affymetrix microarrays , 2002, BMC Bioinformatics.

[12]  S. Welle,et al.  High-abundance mRNAs in human muscle: comparison between young and old. , 2000, Journal of applied physiology.

[13]  J. Oldham,et al.  Sexual dimorphism is associated with decreased expression of processed myostatin in males. , 2003, American journal of physiology. Endocrinology and metabolism.

[14]  K. Nair,et al.  Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[15]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Sam W. Lee,et al.  Role of Pin1 in the Regulation of p53 Stability and p21 Transactivation, and Cell Cycle Checkpoints in Response to DNA Damage* , 2002, The Journal of Biological Chemistry.

[17]  C. Bouchard,et al.  Human variation in skeletal muscle fiber-type proportion and enzyme activities. , 1989, The American journal of physiology.

[18]  J. Lexell Evidence for nervous system degeneration with advancing age. , 1997, The Journal of nutrition.

[19]  A. Luff Age‐associated Changes in the Innervation of Muscle Fibers and Changes in the Mechanical Properties of Motor Units , 1998, Annals of the New York Academy of Sciences.

[20]  A. Prescott,et al.  Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. , 1995, Oncogene.

[21]  L. Kunkel,et al.  Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Hans Joenje,et al.  FANCE: the link between Fanconi anaemia complex assembly and activity , 2002, The EMBO journal.

[23]  J. Leigh,et al.  Relationships between in vivo and in vitro measurements of metabolism in young and old human calf muscles. , 1993, Journal of applied physiology.

[24]  Katsunori Sugimoto,et al.  A Proteomics Approach to Identify Proliferating Cell Nuclear Antigen (PCNA)-binding Proteins in Human Cell Lysates , 2002, The Journal of Biological Chemistry.

[25]  G. Hannon,et al.  Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD , 1995, Science.

[26]  S. Welle,et al.  Stimulation of myofibrillar synthesis by exercise is mediated by more efficient translation of mRNA. , 1999, Journal of applied physiology.

[27]  M. Brown,et al.  Histochemical and enzymatic comparison of the gastrocnemius muscle of young and elderly men and women. , 1992, Journal of gerontology.

[28]  S. Welle Cellular and molecular basis of age-related sarcopenia. , 2002, Canadian journal of applied physiology = Revue canadienne de physiologie appliquee.

[29]  Russell D. Wolfinger,et al.  The contributions of sex, genotype and age to transcriptional variance in Drosophila melanogaster , 2001, Nature Genetics.

[30]  E. Metter,et al.  Skeletal muscle satellite cell populations in healthy young and older men and women , 2000, The Anatomical record.

[31]  D. Hostler,et al.  Fiber Type Composition of the Vastus Lateralis Muscle of Young Men and Women , 2000 .

[32]  S. Lamberts,et al.  The endocrinology of aging. , 1997, Science.

[33]  M. Groudine,et al.  Reconstitution of a MEC1-independent checkpoint in yeast by expression of a novel human fork head cDNA , 1997, Molecular and cellular biology.

[34]  E. Metter,et al.  Influence of age, sex, and strength training on human muscle gene expression determined by microarray. , 2002, Physiological genomics.

[35]  C. K. Lee,et al.  Gene expression profile of aging and its retardation by caloric restriction. , 1999, Science.

[36]  Jiro Kikuchi,et al.  Identification of novel p53-binding proteins by biomolecular interaction analysis combined with tandem mass spectrometry , 2003, Molecular biotechnology.

[37]  U. Lass,et al.  Elevated p21 mRNA level in skeletal muscle of DMD patients and mdx mice indicates either an exhausted satellite cell pool or a higher p21 expression in dystrophin-deficient cells per se , 2000, Journal of Molecular Medicine.

[38]  H. Soreq,et al.  Pre‐mRNA splicing modulations in senescence , 2002, Aging cell.

[39]  K. Walsh,et al.  MyoD-induced expression of p21 inhibits cyclin-dependent kinase activity upon myocyte terminal differentiation , 1995, Molecular and cellular biology.

[40]  A. D’Andrea,et al.  Fanconi anemia and DNA repair. , 2001, Human molecular genetics.

[41]  M. O’Reilly,et al.  The cyclin-dependent kinase inhibitor p21 protects the lung from oxidative stress. , 2001, American journal of respiratory cell and molecular biology.

[42]  R. Roubenoff Catabolism of aging: is it an inflammatory process? , 2003, Current opinion in clinical nutrition and metabolic care.

[43]  T. Zimmers,et al.  Induction of Cachexia in Mice by Systemically Administered Myostatin , 2002, Science.

[44]  S. Volinia,et al.  The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults , 2002, Nature.

[45]  P. O'Connor,et al.  Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. , 1994, Science.

[46]  D B Allison,et al.  Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[47]  R. Hewick,et al.  Regulation of myostatin in vivo by growth and differentiation factor-associated serum protein-1: a novel protein with protease inhibitor and follistatin domains. , 2003, Molecular endocrinology.

[48]  W. Evans,et al.  Aged human muscle demonstrates an altered gene expression profile consistent with an impaired response to exercise , 2000, Mechanisms of Ageing and Development.

[49]  R. Paules,et al.  DNA damage and cell cycle checkpoints , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[50]  H. Tanke,et al.  Induction of p21 mRNA Synthesis After Short-wavelength UV Light Visualized in Individual Cells by RNA FISH , 2002, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[51]  Se-Jin Lee,et al.  Regulation of myostatin activity and muscle growth , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[52]  T. Cooper,et al.  Pre-mRNA splicing and human disease. , 2003, Genes & development.

[53]  R. Hewick,et al.  The Myostatin Propeptide and the Follistatin-related Gene Are Inhibitory Binding Proteins of Myostatin in Normal Serum* , 2002, The Journal of Biological Chemistry.

[54]  S. Welle,et al.  Insulin-like growth factor-1 and myostatin mRNA expression in muscle: comparison between 62–77 and 21–31yr old men , 2002, Experimental Gerontology.

[55]  I. Hickson,et al.  DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. , 2001, Human molecular genetics.

[56]  Yoichi Taya,et al.  DNA Damage-Induced Phosphorylation of p53 Alleviates Inhibition by MDM2 , 1997, Cell.

[57]  P. Mecocci,et al.  Age-dependent increases in oxidative damage to DNA, lipids, and proteins in human skeletal muscle. , 1999, Free radical biology & medicine.

[58]  Geert J. P. L. Kops,et al.  Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress , 2002, Nature.