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Contraction-stimulated glucose transport in muscle is controlled by AMPK and mechanical stress but not sarcoplasmatic reticulum Ca(2+) release.

Jensen TE, Sylow L, Rose AJ, Madsen AB, Angin Y, Maarbjerg SJ, Richter EA - Mol Metab (2014)

Bottom Line: The prevailing concept implicates Ca(2+) as a key feed forward regulator of glucose transport with secondary fine-tuning by metabolic feedback signals through proteins such as AMPK.Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress-activated signals.These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport during muscle contraction, and call for a major reconsideration of the established Ca(2+) centric paradigm.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, 2100 Copenhagen, Denmark.

ABSTRACT
Understanding how muscle contraction orchestrates insulin-independent muscle glucose transport may enable development of hyperglycemia-treating drugs. The prevailing concept implicates Ca(2+) as a key feed forward regulator of glucose transport with secondary fine-tuning by metabolic feedback signals through proteins such as AMPK. Here, we demonstrate in incubated mouse muscle that Ca(2+) release is neither sufficient nor strictly necessary to increase glucose transport. Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress-activated signals. Furthermore, artificial stimulation of AMPK combined with passive stretch of muscle is additive and sufficient to elicit the full contraction glucose transport response. These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport during muscle contraction, and call for a major reconsideration of the established Ca(2+) centric paradigm.

No MeSH data available.


Related in: MedlinePlus

Neither insulin nor AICAR-stimulated signalling or glucose transport are affected by myosin ATPase blockers. A) Representative western blots and quantifications of control and insulin-stimulated (60 nM, 20 min) phosphorylations in SOL and EDL and B) corresponding 2DG transport in SOL and EDL. n = 9, ***p < 0.001 ANOVA main-effect of insulin. C) Representative western blots and quantifications of control vs. AICAR-stimulated (2 mM, 40 min) phosphorylations and D) corresponding 2DG transport (right) in EDL, n = 9, ***p < 0.001 ANOVA main-effect of AICAR. Data are mean ± S.E.M.
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fig2: Neither insulin nor AICAR-stimulated signalling or glucose transport are affected by myosin ATPase blockers. A) Representative western blots and quantifications of control and insulin-stimulated (60 nM, 20 min) phosphorylations in SOL and EDL and B) corresponding 2DG transport in SOL and EDL. n = 9, ***p < 0.001 ANOVA main-effect of insulin. C) Representative western blots and quantifications of control vs. AICAR-stimulated (2 mM, 40 min) phosphorylations and D) corresponding 2DG transport (right) in EDL, n = 9, ***p < 0.001 ANOVA main-effect of AICAR. Data are mean ± S.E.M.

Mentions: We were initially concerned that Bleb in particular might have off-target effects since MyoII has been implicated in insulin-stimulated GLUT4 translocation and glucose transport in adipocytes [19]. However, neither insulin nor AICAR-stimulated signalling (Figure 2A+C) or glucose transport (Figure 2B+D) were inhibited by BTS + Bleb, suggesting that the effects of myosin ATPase inhibition are specific to contraction.


Contraction-stimulated glucose transport in muscle is controlled by AMPK and mechanical stress but not sarcoplasmatic reticulum Ca(2+) release.

Jensen TE, Sylow L, Rose AJ, Madsen AB, Angin Y, Maarbjerg SJ, Richter EA - Mol Metab (2014)

Neither insulin nor AICAR-stimulated signalling or glucose transport are affected by myosin ATPase blockers. A) Representative western blots and quantifications of control and insulin-stimulated (60 nM, 20 min) phosphorylations in SOL and EDL and B) corresponding 2DG transport in SOL and EDL. n = 9, ***p < 0.001 ANOVA main-effect of insulin. C) Representative western blots and quantifications of control vs. AICAR-stimulated (2 mM, 40 min) phosphorylations and D) corresponding 2DG transport (right) in EDL, n = 9, ***p < 0.001 ANOVA main-effect of AICAR. Data are mean ± S.E.M.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209358&req=5

fig2: Neither insulin nor AICAR-stimulated signalling or glucose transport are affected by myosin ATPase blockers. A) Representative western blots and quantifications of control and insulin-stimulated (60 nM, 20 min) phosphorylations in SOL and EDL and B) corresponding 2DG transport in SOL and EDL. n = 9, ***p < 0.001 ANOVA main-effect of insulin. C) Representative western blots and quantifications of control vs. AICAR-stimulated (2 mM, 40 min) phosphorylations and D) corresponding 2DG transport (right) in EDL, n = 9, ***p < 0.001 ANOVA main-effect of AICAR. Data are mean ± S.E.M.
Mentions: We were initially concerned that Bleb in particular might have off-target effects since MyoII has been implicated in insulin-stimulated GLUT4 translocation and glucose transport in adipocytes [19]. However, neither insulin nor AICAR-stimulated signalling (Figure 2A+C) or glucose transport (Figure 2B+D) were inhibited by BTS + Bleb, suggesting that the effects of myosin ATPase inhibition are specific to contraction.

Bottom Line: The prevailing concept implicates Ca(2+) as a key feed forward regulator of glucose transport with secondary fine-tuning by metabolic feedback signals through proteins such as AMPK.Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress-activated signals.These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport during muscle contraction, and call for a major reconsideration of the established Ca(2+) centric paradigm.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, 2100 Copenhagen, Denmark.

ABSTRACT
Understanding how muscle contraction orchestrates insulin-independent muscle glucose transport may enable development of hyperglycemia-treating drugs. The prevailing concept implicates Ca(2+) as a key feed forward regulator of glucose transport with secondary fine-tuning by metabolic feedback signals through proteins such as AMPK. Here, we demonstrate in incubated mouse muscle that Ca(2+) release is neither sufficient nor strictly necessary to increase glucose transport. Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress-activated signals. Furthermore, artificial stimulation of AMPK combined with passive stretch of muscle is additive and sufficient to elicit the full contraction glucose transport response. These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport during muscle contraction, and call for a major reconsideration of the established Ca(2+) centric paradigm.

No MeSH data available.


Related in: MedlinePlus