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Aging affects the transcriptional regulation of human skeletal muscle disuse atrophy.

Suetta C, Frandsen U, Jensen L, Jensen MM, Jespersen JG, Hvid LG, Bayer M, Petersson SJ, Schrøder HD, Andersen JL, Heinemeier KM, Aagaard P, Schjerling P, Kjaer M - PLoS ONE (2012)

Bottom Line: 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 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Sports Medicine and Center for Healthy Aging, University of Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark. csuetta@gmail.com

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.

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Changes in the transcriptional status of FoxO1, FoxO3 and FoxO4 as a result of immobility-induced muscle disuse.A–C. The mRNA level of FoxO1, FoxO3 and FoxO4 was determined using qRT-PCR. No up-regulation in the mRNA expression levels in any of these three genes was observed during the initial phase of immobility, in contrast, a general down-regulation in all three genes was observed in both young and aged muscle at the 4 d time point, potentially reflecting a negative feedback signal from high presence of active FoxO protein in the muscle cell. However, it is difficult to interpret the role of FoxO in the present study since the phosphorylated forms of FoxO were not measured. * Time effect, p<0.05 bar indicates young and old within time point. Data are geometric means ± back-transformed SEM.
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pone-0051238-g005: Changes in the transcriptional status of FoxO1, FoxO3 and FoxO4 as a result of immobility-induced muscle disuse.A–C. The mRNA level of FoxO1, FoxO3 and FoxO4 was determined using qRT-PCR. No up-regulation in the mRNA expression levels in any of these three genes was observed during the initial phase of immobility, in contrast, a general down-regulation in all three genes was observed in both young and aged muscle at the 4 d time point, potentially reflecting a negative feedback signal from high presence of active FoxO protein in the muscle cell. However, it is difficult to interpret the role of FoxO in the present study since the phosphorylated forms of FoxO were not measured. * Time effect, p<0.05 bar indicates young and old within time point. Data are geometric means ± back-transformed SEM.

Mentions: There was no up-regulation in the mRNA expression levels of any of the three isoforms of the FoxO family in skeletal muscle (FoxO1, FoxO3 and FoxO4) after 4 days or 14 days of immobilization. In fact, a general down-regulation in all three genes was observed in both young and aged muscle after 4 days of unloading but not at the 14 days time point (Figure 5, A–C). No age related differences were observed at any time point (Figure 5, A–C).


Aging affects the transcriptional regulation of human skeletal muscle disuse atrophy.

Suetta C, Frandsen U, Jensen L, Jensen MM, Jespersen JG, Hvid LG, Bayer M, Petersson SJ, Schrøder HD, Andersen JL, Heinemeier KM, Aagaard P, Schjerling P, Kjaer M - PLoS ONE (2012)

Changes in the transcriptional status of FoxO1, FoxO3 and FoxO4 as a result of immobility-induced muscle disuse.A–C. The mRNA level of FoxO1, FoxO3 and FoxO4 was determined using qRT-PCR. No up-regulation in the mRNA expression levels in any of these three genes was observed during the initial phase of immobility, in contrast, a general down-regulation in all three genes was observed in both young and aged muscle at the 4 d time point, potentially reflecting a negative feedback signal from high presence of active FoxO protein in the muscle cell. However, it is difficult to interpret the role of FoxO in the present study since the phosphorylated forms of FoxO were not measured. * Time effect, p<0.05 bar indicates young and old within time point. Data are geometric means ± back-transformed SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3526599&req=5

pone-0051238-g005: Changes in the transcriptional status of FoxO1, FoxO3 and FoxO4 as a result of immobility-induced muscle disuse.A–C. The mRNA level of FoxO1, FoxO3 and FoxO4 was determined using qRT-PCR. No up-regulation in the mRNA expression levels in any of these three genes was observed during the initial phase of immobility, in contrast, a general down-regulation in all three genes was observed in both young and aged muscle at the 4 d time point, potentially reflecting a negative feedback signal from high presence of active FoxO protein in the muscle cell. However, it is difficult to interpret the role of FoxO in the present study since the phosphorylated forms of FoxO were not measured. * Time effect, p<0.05 bar indicates young and old within time point. Data are geometric means ± back-transformed SEM.
Mentions: There was no up-regulation in the mRNA expression levels of any of the three isoforms of the FoxO family in skeletal muscle (FoxO1, FoxO3 and FoxO4) after 4 days or 14 days of immobilization. In fact, a general down-regulation in all three genes was observed in both young and aged muscle after 4 days of unloading but not at the 14 days time point (Figure 5, A–C). No age related differences were observed at any time point (Figure 5, A–C).

Bottom Line: 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 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Sports Medicine and Center for Healthy Aging, University of Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark. csuetta@gmail.com

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.

Show MeSH
Related in: MedlinePlus