1 Department of Clinical Medicine - Department of Paediatrics, Department of Clinical Medicine, Health, Aarhus University2 Institut for Klinisk Medicin3 Faculty of Science, Aarhus University, Aarhus University4 Department of Language, Literature and Culture, Faculty of Humanities, Aarhus University, Aarhus University5 Department of Policy Analysis, National Environmental Research Institute, Aarhus University, Aarhus University6 Integrative Physiology7 Institut for Idræt og Biomekanik8 Afd. for Systembiologisk forskning9 Patologi10 unknown11 SUND ph.d. skole12 Undervisningsudvalg13 Department of Clinical Medicine - Department of Paediatrics, Department of Clinical Medicine, Health, Aarhus University
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-1a and PGC-1ß (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.