title: Aging affects the transcriptional regulation of human skeletal muscle disuse atrophy.
abstract: Important insights concerning the molecular basis of skeletal muscle disuse-atrophy and aging related muscle loss have been obtained in cell culture and animal models, but these regulatory signaling pathways have not previously been studied in aging human muscle. In the present study, muscle atrophy was induced by immobilization in healthy old and young individuals to study the time-course and transcriptional factors underlying human skeletal muscle atrophy. The results reveal that irrespectively of age, mRNA expression levels of MuRF-1 and Atrogin-1 increased in the very initial phase (2-4 days) of human disuse-muscle atrophy along with a marked reduction in PGC-1α and PGC-1β (1-4 days) and a ~10% decrease in myofiber size (4 days). Further, an age-specific decrease in Akt and S6 phosphorylation was observed in young muscle within the first days (1-4 days) of immobilization. In contrast, Akt phosphorylation was unchanged in old muscle after 2 days and increased after 4 days of immobilization. Further, an age-specific down-regulation of MuRF-1 and Atrogin-1 expression levels was observed following 2 weeks of immobilization, along with a slowing atrophy response in aged skeletal muscle. Neither the immediate loss of muscle mass, nor the subsequent age-differentiated signaling responses could be explained by changes in inflammatory mediators, apoptosis markers or autophagy indicators. Collectively, these findings indicate that the time-course and regulation of human skeletal muscle atrophy is age dependent, leading to an attenuated loss in aging skeletal muscle when exposed to longer periods of immobility-induced disuse.
authors.affiliation: Institute of Sports Medicine and Center for Healthy Aging, University of Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark. csuetta@gmail.com
authors.forename: Charlotte
authors.initials: C
authors.lastname: Suetta
authors.forename: Ulrik
authors.initials: U
authors.lastname: Frandsen
authors.forename: Line
authors.initials: L
authors.lastname: Jensen
authors.forename: Mette Munk
authors.initials: MM
authors.lastname: Jensen
authors.forename: Jakob G
authors.initials: JG
authors.lastname: Jespersen
authors.forename: Lars G
authors.initials: LG
authors.lastname: Hvid
authors.forename: Monika
authors.initials: M
authors.lastname: Bayer
authors.forename: Stine J
authors.initials: SJ
authors.lastname: Petersson
authors.forename: Henrik D
authors.initials: HD
authors.lastname: Schrøder
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Andersen
authors.forename: Katja M
authors.initials: KM
authors.lastname: Heinemeier
authors.forename: Per
authors.initials: P
authors.lastname: Aagaard
authors.forename: Peter
authors.initials: P
authors.lastname: Schjerling
authors.forename: Michael
authors.initials: M
authors.lastname: Kjaer
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics; D053580:Muscle Strength / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020966:Muscular Disorders, Atrophic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016328:NF-kappa B / Q000378:metabolism; D009929:Organ Size; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D059467:Transcriptome; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055815:Young Adult
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D007334:Insulin-Like Growth Factor I; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt