Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis

Christopher S Fry, Micah J Drummond, Erin L Glynn, Jared M Dickinson, David M Gundermann, Kyle L Timmerman, Dillon K Walker, Shaheen Dhanani, Elena Volpi, Blake B Rasmussen, Christopher S Fry, Micah J Drummond, Erin L Glynn, Jared M Dickinson, David M Gundermann, Kyle L Timmerman, Dillon K Walker, Shaheen Dhanani, Elena Volpi, Blake B Rasmussen

Abstract

Background: Sarcopenia, the loss of skeletal muscle mass during aging, increases the risk for falls and dependency. Resistance exercise (RE) training is an effective treatment to improve muscle mass and strength in older adults, but aging is associated with a smaller amount of training-induced hypertrophy. This may be due in part to an inability to stimulate muscle-protein synthesis (MPS) after an acute bout of RE. We hypothesized that older adults would have impaired mammalian target of rapamycin complex (mTORC)1 signaling and MPS response compared with young adults after acute RE.

Methods: We measured intracellular signaling and MPS in 16 older (mean 70 ± 2 years) and 16 younger (27 ± 2 years) subjects. Muscle biopsies were sampled at baseline and at 3, 6 and 24 hr after exercise. Phosphorylation of regulatory signaling proteins and MPS were determined on successive muscle biopsies by immunoblotting and stable isotopic tracer techniques, respectively.

Results: Increased phosphorylation was seen only in the younger group (P< 0.05) for several key signaling proteins after exercise, including mammalian target of rapamycin (mTOR), ribosomal S6 kinase (S6K)1, eukaryotic initiation factor 4E-binding protein (4E-BP)1 and extracellular signal-regulated kinase (ERK)1/2, with no changes seen in the older group (P >0.05). After exercise, MPS increased from baseline only in the younger group (P< 0.05), with MPS being significantly greater than that in the older group (P <0.05).

Conclusions: We conclude that aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis. These age-related differences may contribute to the blunted hypertrophic response seen after resistance-exercise training in older adults, and highlight the mTORC1 pathway as a key therapeutic target to prevent sarcopenia.

Figures

Figure 1
Figure 1
Study design. Blood was sampled throughout the study and muscle samples were taken at the times indicated (X). Exercise was performed after the second biopsy.
Figure 2
Figure 2
Akt, mammalian target of rapamycin (mTOR), S6 kinase (S6K)1, eukaryotic initiation factor 4E-binding protein (4E-BP)1. Data represent phosphorylation fold change of Akt at Ser473 (A), mTOR at Ser2448 (B), S6K1 at Thr389 (C) and 4E-BP1 at Thr37/46 (D) at baseline, 3, 6 and 24 hours after exercise. Representative immunoblot images are shown. Significantly different from *baseline (P <0.05); #from older subjects (P <0.05).
Figure 3
Figure 3
Extracellular signal-regulated kinase (ERK)1/2 and ribosomal protein (rp)S6. Data represent phosphorylation fold change of (A) ERK1/2 at Thr202/Tyr204 and (B) rpS6 at Ser235/236 at baseline, and 3, 6 and 24 hours after exercise. Representative immunoblot images are shown. *Significantly different from baseline (P <0.05).
Figure 4
Figure 4
Total protein content. Representative immunoblot images for Akt, mammalian target of rapamycin (mTOR), S6 kinase (S6K)1,, eukaryotic initiation factor 4E-binding protein (4E-BP)1, extracellular signal-regulated kinase (ERK)1/2, ribosomal protein (rp)S6 and α-tubulin. Protein content did not change during postexercise recovery in either group (P> 0.05).
Figure 5
Figure 5
Mixed muscle protein fractional synthetic rate (FSR). Muscle protein synthesis as expressed by the mixed muscle FSR (%/hour) in younger and older subjects at rest and at 3, 6 and 24 hours after exercise. *Main effect for time (P <0.05); #significantly different from older subjects (P <0.05).
Figure 6
Figure 6
Relationship between muscle protein fractional synthetic rate (FRS) and extent of phosphorylation of S6 kinase (S6K)1 and mammalian target of rapamycin (mTOR), at 24 hours after exercise. There was a significant relationship (P = 0.01) between the degree of phosphorylation of mTOR (Ser2448) (AU) and mixed muscle protein fractional synthetic rate (%/hour) at 24 hours after exercise in (A) the young group only, with (B) no significant relationship seen in the older group (P = 0.71). There was a significant relationship (P = 0.04) between the degree of phosphorylation of S6K1 (Thr389) (AU) and mixed muscle protein fractional synthetic rate (%/hour) at 24 hours after exercise in (C) young group only, with (D) no significant relationship seen in the older group (P = 0.69). Note: some points overlaid.

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