AMP-activated Protein Kinase Suppresses Protein Synthesis in Rat Skeletal Muscle through Down-regulated Mammalian Target of Rapamycin (mTOR) Signaling*

By D. Bolster, Stephen Crozier, S. Kimball, L. Jefferson. Journal of Biological Chemistry, 2002

893 citations recorded by the source corpus.

AMP-activated protein kinase (AMPK) is viewed as an energy sensor that acts to modulate glucose uptake and fatty acid oxidation in skeletal muscle. Given that protein synthesis is a high energy-consuming process, it may be transiently depressed during cellular energy stress. Thus, the intent of this investigation was to examine whether AMPK activation modulates the translational control of protein synthesis in skeletal muscle. Injections of 5-aminoimidazole-4-carboxamide 1-β-d-ribonucleoside (AICAR) were used to activate AMPK in male rats. The activity of α1 AMPK remained unchanged in gastrocnemius muscle from AICAR-treated animals compared with controls, whereas α2AMPK activity was significantly increased (51%). AICAR treatment resulted in a reduction in protein synthesis to 45% of the control value. This depression was associated with decreased activation of protein kinases in the mammalian target of rapamycin (mTOR) signal transduction pathway as evidenced by reduced phosphorylation of protein kinase B on Ser473, mTOR on Ser2448, ribosomal protein S6 kinase on Thr389, and eukaryotic initiation factor eIF4E-binding protein on Thr37. A reduction in eIF4E associated with eIF4G to 10% of the control value was also noted. In contrast, eIF2B activity remained unchanged in response to AICAR treatment and therefore would not appear to contribute to the depression in protein synthesis. This is the first investigation to demonstrate changes in translation initiation and skeletal muscle protein synthesis in response to AMPK activation.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/a9adc55cdb4ebfcca54070824d1fa52657764d43

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In Molecular Biology

1. D. Hardie
2. K. Guan
3. G. Steinberg
4. David M. Sabatini
5. Bruce E. Kemp
6. K. Inoki
7. J. Zierath
8. Tianqing Zhu

In Surgery

1. D. Hardie
2. G. Steinberg
3. Bruce E. Kemp
4. K. Guan
5. K. Inoki
6. Tianqing Zhu
7. J. Zierath
8. R. Shaw

Citations in the corpus

• Resistance exercise increases AMPK activity and reduces 4E‐BP1 phosphorylation and protein synthesis in human skeletal muscle (2006, background): “In addition, more recent work has shown that artificially activating AMPK in rodent muscle suppresses muscle protein synthesis by inhibiting the mammalian target of rapamycin (mTOR) signalling pathway (Bolster et al. 2002).”
• The AMP-activated protein kinase pathway – new players upstream and downstream (2004, background): “…al., 2002; Browne et al., 2004), which switches off the elongation step in translation; and (2) inhibition of the target of rapamycin (TOR) pathway (Bolster et al., 2002; Krause et al., 2002; Kimura et al., 2003), which is a major positive stimulus for protein synthesis, cell growth and cell size.”
• Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle (2008, background): “…et al. 1990; Sheffield-Moore et al. 2004) we proposed that we would observe increases, albeit one that may have been delayed due to AMPK activation (Bolster et al. 2002; Atherton et al. 2005; Thomson et al. 2008), in both mitochondrial and myofibrillar protein synthesis following endurance…”
• TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. (2006, background): “AMPK inhibits protein synthesis, one of the most energy-consuming cellular activities, by inhibiting both translation initiation and elongation (Bolster et al., 2002; Horman et al., 2002).”
• AMPK in Health and Disease. (2009, background): “Since the constitutively active AMPK fragment 1 (1-312) is not activated by the PT1 compound, it is proposed that PT1 acts by reversing the autoinhibition of the AIS (313-335).”
• Exercise metabolism and the molecular regulation of skeletal muscle adaptation. (2013, background): “In skeletal muscle, acute AMPK activation suppresses glycogen synthesis (Carling and Hardie, 1989) and protein synthesis (Bolster et al., 2002), but promotes Cell Metabolism 17, February 5, 2013 ª2013 Elsevier Inc. 169 glucose transport (Merrill et al., 1997) and lipid metabolism (Winder and…”