title: Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia.
abstract: Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months. These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes, and functional annotation analysis identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/pathways associated with neuromuscular junction patency (providing molecular evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation. Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins. Together, these findings suggest that therapeutic approaches that simultaneously stimulate mitochondrogenesis and reduce muscle proteolysis and inflammation have potential for treating sarcopenia.
authors.affiliation: Muscle Diseases Group, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Chikwendu
authors.initials: C
authors.lastname: Ibebunjo
authors.forename: Joel M
authors.initials: JM
authors.lastname: Chick
authors.forename: Tracee
authors.initials: T
authors.lastname: Kendall
authors.forename: John K
authors.initials: JK
authors.lastname: Eash
authors.forename: Christine
authors.initials: C
authors.lastname: Li
authors.forename: Yunyu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chad
authors.initials: C
authors.lastname: Vickers
authors.forename: Zhidan
authors.initials: Z
authors.lastname: Wu
authors.forename: Brian A
authors.initials: BA
authors.lastname: Clarke
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.forename: Joseph
authors.initials: J
authors.lastname: Cruz
authors.forename: Brigitte
authors.initials: B
authors.lastname: Fournier
authors.forename: Sophie
authors.initials: S
authors.lastname: Brachat
authors.forename: Sabine
authors.initials: S
authors.lastname: Gutzwiller
authors.forename: QiCheng
authors.initials: Q
authors.lastname: Ma
authors.forename: Judit
authors.initials: J
authors.lastname: Markovits
authors.forename: Michelle
authors.initials: M
authors.lastname: Broome
authors.forename: Michelle
authors.initials: M
authors.lastname: Steinkrauss
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Skuba
authors.forename: Jean-Rene
authors.initials: JR
authors.lastname: Galarneau
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics; D004734:Energy Metabolism; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D016014:Linear Models; D008297:Male; D046228:Microarray Analysis; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053580:Muscle Strength / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011180:Postmortem Changes; D020543:Proteome / Q000032:analysis*; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055948:Sarcopenia / Q000473:pathology*; D015398:Signal Transduction; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D004272:DNA, Mitochondrial; D020543:Proteome