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Early signaling responses to divergent exercise stimuli in skeletal muscle from well-trained humans

Vernon G. Coffey^*,1, Zhihui Zhong^,1, Anthony Shield^*, Benedict J. Canny, Alexander V. Chibalin, Juleen R. Zierath and John A. Hawley^*,2

^* School of Medical Sciences, RMIT University, Victoria, Australia;
Department of Surgical Sciences, Karolinska Institutet, Stockholm, Sweden; and
Department of Physiology, Monash University, Victoria, Australia

²Correspondence: School of Medical Sciences, RMIT University, PO Box 71, Bundoora, Victoria 3083, Australia. E-mail: john.hawley{at}rmit.edu.au

1. PRINCIPAL AIMS

Skeletal muscle from strength- and endurance-trained individuals represents diverse adaptive states. In this regard, AMPK-PGC-1 signaling has been proposed to mediate several adaptations to endurance training, while up-regulation of the Akt-TSC2-mTOR pathway may underlie increased protein synthesis after resistance exercise. In the present study we determined whether early signaling events in skeletal muscle that are elicited in response to different types of contractile stimuli (e.g., endurance and strength training) mediate specific adaptations that accrue after chronic exercise. Using a unique design in which athletes from different training backgrounds (i.e., chronically endurance- or strength-trained) undertook exercise in their habitual training mode, and "crossed over" to perform an acute bout in a non-familiar exercise discipline, we characterize the acute signaling events underlying the specific adaptations to diverse modes of contractile activity associated with endurance and strength training.

2. PRINCIPAL FINDINGS

1. Prior training history blunts the normal exercise-specific increase in AMPK phosphorylation
Phosphorylation of AMPK increased immediately after cycling exercise in strength-trained (54%; P<0.05, Fig. 1 A), but not endurance-trained subjects. Conversely, AMPK phosphorylation was increased immediately post-exercise in endurance- (114%; P<0.05, Fig. 1B ), but not strength-trained subjects after resistance exercise. These changes in AMPK phosphorylation in human skeletal muscle in vivo are in complete contrast to recent results in rodent skeletal muscle, whereby signaling responses were determined in response to in vitro electrical stimulation.

View larger version (28K): [in this window] [in a new window]   Figure 1. AMPK phosphorylation in vastus lateralis muscle of strength-trained (ST) and endurance-trained (ET) subjects in response to 60 min cycling at 70% VO2peak (A) and 8 x 5 maximal isokinetic leg extensions (B). Values are group means (±SE) at rest, immediately post-exercise (Post) and 3 h post-exercise (3 h). *Significant difference rest vs. post (*P<0.05); Significant difference post vs. 3 h (P<0.05).

2. Prior training history blunts the normal exercise-specific increase in PGC-1 protein expression
PGC-1 mRNA was increased to a similar extent after cycling in both endurance-trained (8.5-fold, P<0.001) and strength-trained subjects (10-fold increase, P<0.001). However, PGC-1 protein content after 3 h recovery from cycling or resistance exercise was unchanged in strength- and endurance-trained subjects.

3. Exercise-induced Akt and TSC2 phosphorylation
After cycling exercise, Akt phosphorylation on Ser⁴⁷³ was increased in endurance- (50%; P<0.05), but not strength-trained subjects (Fig. 2 A). The level of Akt phosphorylation on Thr³⁰⁸ was unchanged. After 3 h of recovery, Akt phosphorylation decreased below resting values in endurance-trained subjects (67%; P<0.01). Akt phosphorylation was similar between strength- and endurance-trained subjects after resistance exercise (Fig. 2B ). TSC2 phosphorylation was unaltered after cycle exercise in either strength- or endurance-trained subjects (Fig. 2C ). However, after resistance exercise, TSC2 phosphorylation was decreased in endurance-trained subjects immediately post-exercise (47%; P<0.05), an effect that persisted for 3 h recovery (40%; P<0.05, Fig. 2D ).

View larger version (18K): [in this window] [in a new window]   Figure 2. pAkt (A, B) and pTSC2 (C, D) phosphorylation in vastus lateralis muscle of strength-trained (ST) and endurance-trained (ET) subjects in response to 60 min cycling at 70% VO2peak (A, C) and 8 x 5 maximal isokinetic leg extensions (B, D). Values are group means (±SE) at rest, immediately post-exercise (Post) and 3 h post-exercise (3 h). *Significant difference rest vs. post (*P<0.05); Significant difference rest vs. 3 h (P<0.05, P<0.01); Significant difference post vs. 3 h (P<0.001).

4. Phosphorylation of S6 protein in response to exercise
Phosphorylation of S6 protein, a substrate for p70 S6K, was increased immediately after resistance exercise in endurance-trained (129%; P<0.05), but not strength-trained subjects.

3. CONCLUSIONS AND SIGNIFICANCE

While information pertaining to the subsets of genes and putative signaling pathways activated in response to different modes of contraction in humans is emerging, the mechanism for adaptive changes in skeletal muscle in response to training is incompletely resolved. Moreover, whether prior contractile activity (i.e., training history) affects the acute responses to divergent exercise stimuli is unknown. The results from the current study provide the first evidence that human skeletal muscle retains the capacity to respond to divergent contractile stimuli and that a degree of "response plasticity" is conserved at opposite ends of the endurance-hypertrophic adaptation continuum (Fig. 3 ). Although selective activation of the AMPK-PGC-1 or PKB-TSC2-mTOR signaling pathways has been proposed to explain many of the specific adaptive responses to endurance or resistance training during in vitro electrically stimulated muscle contractions, our in vivo findings provide little evidence for the putative AMPK-PKB(Akt) switch. Indeed, prior endurance- or strength-training appears to attenuate some of the signaling specific responses involved in the adaptation to single mode training.

View larger version (25K): [in this window] [in a new window]   Figure 3. Schematic of the putative signaling pathways that may mediate the mode-specific skeletal muscle adaptations to endurance- and strength training. Up-regulation of AMPK-PGC-1 signaling has been proposed to underlie several adaptations that culminate in mitochondrial biogenesis and an "endurance trained" phenotype. In contrast, up-regulation of the Akt-TSC2-mTOR pathway may mediate the increased protein synthesis observed after resistance exercise. These two states represent extremes of the "adaptation continuum." Our results suggest that prior endurance- or strength-training attenuates some of the signaling-specific responses involved in the adaptation to single mode training.

FOOTNOTES

¹ Authors made equal contribution

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-4809fje;

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