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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adult
-
Aged
-
Aging / genetics*
-
Aging / metabolism
-
Aging / pathology
-
Aging / physiology
-
Apoptosis / genetics
-
Autophagy / genetics
-
Cytokines / metabolism
-
Forkhead Transcription Factors / genetics
-
Heat-Shock Proteins / genetics
-
Humans
-
Insulin-Like Growth Factor I / metabolism
-
Male
-
Middle Aged
-
Muscle Contraction / genetics
-
Muscle Fibers, Skeletal / metabolism
-
Muscle Fibers, Skeletal / pathology
-
Muscle Proteins / genetics
-
Muscle Strength / genetics
-
Muscle, Skeletal / metabolism*
-
Muscle, Skeletal / pathology
-
Muscle, Skeletal / physiopathology
-
Muscular Disorders, Atrophic / genetics*
-
Muscular Disorders, Atrophic / metabolism
-
Muscular Disorders, Atrophic / pathology
-
Muscular Disorders, Atrophic / physiopathology*
-
NF-kappa B / metabolism
-
Organ Size
-
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
-
Proto-Oncogene Proteins c-akt / metabolism
-
Signal Transduction / genetics
-
Transcription Factors / genetics
-
Transcription, Genetic / genetics*
-
Transcriptome*
-
Tripartite Motif Proteins
-
Ubiquitin-Protein Ligases / genetics
-
Young Adult
Substances
-
Cytokines
-
Forkhead Transcription Factors
-
Heat-Shock Proteins
-
Muscle Proteins
-
NF-kappa B
-
PPARGC1A protein, human
-
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
-
Transcription Factors
-
Tripartite Motif Proteins
-
Insulin-Like Growth Factor I
-
TRIM63 protein, human
-
Ubiquitin-Protein Ligases
-
Proto-Oncogene Proteins c-akt
Grants and funding
The study was supported by grants from the Danish National Research Council, the Danish Rheumatology Association, Faculty of Health Sciences, University of Copenhagen, The Danish Ministry of Culture, MYOAGE (nr. 223576) funded by the European Commission under FP7, The Nordea Foundation and the Lundbeck Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.