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Are exercise-induced genes induced by exercise?

Department of Molecular Muscle Biology, Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark

¹Correspondence: Department of Molecular Muscle Biology, Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen 2100, Denmark. E-mail: viridis{at}biobase.dk

SPECIFIC AIMS

The frequent use of preintervention control samples for human in vivo studies of gene expression requires that such controls be representative for postintervention sampling. The purpose of this study was to investigate whether such a control strategy sufficiently excludes factors other than the specified intervention in question as an influence of gene expression on a number of selected genes.

PRINCIPAL FINDINGS

1. Gene expression of some transcription factors and cell cycle related factors are induced in nonexercising as well as exercising human subjects
Seven male subjects performed a standard single bout exercise protocol (exercise group) including muscle biopsy sampling before and after exercise (Fig. 1 ). Another 7 subjects performed no exercise, but completed all other parts of the protocol (control group). mRNA levels were determined in muscle biopsies taken before and after the exercise period by Northern blot analysis. When compared with the presample, transcription factor PGC-1 was induced during recovery in exercised subjects, but not in nonexercised subjects (Fig. 2 A). The myogenic regulatory family (MRF) member myogenin showed a similar expression pattern but no significant change was observed between groups (Fig. 2C ). MRF family member MyoD (Fig. 2B ) and the cell cycle-related gene p21 (Fig. 2D ) were induced both in exercised and nonexercised subjects. No difference between groups was observed.

View larger version (11K): [in this window] [in a new window]   Figure 1. A) Study design. Graph of protocol including time-points for meals and for biopsy sampling prior to and in the recovery phase from a single 3 h exercise bout. The 8:00 p.m. meals on days 1 and 2 were free of choice, while the 7:00 a.m. meal on day 2 was high-glycemic. B) Biopsy sampling. 6 biopsies were sampled: 2 in each of 3 incision holes in a predetermined order.

View larger version (11K): [in this window] [in a new window]   Figure 2. mRNA levels for transcription factor and cell cycle related genes. A) PGC1-; B) MyoD; C) myogenin; D) p21. Gray and white bars represents exercised and control subjects, respectively. Results are presented on a log scale as fold changes compared with "pre" level during 20 h of recovery. *Significant changes (P>0.05) for either group at a specific time point. Significant changes (P>0.05) between groups at a specific time point. Result of ANOVA (exercise time) is shown in upper right corner of each panel.

2. Gene expression patterns of stress-related genes are influenced by trauma caused by repeated biopsy sampling
To investigate a potential stress response, a number of heat shock protein (HSP) genes were included in our analysis. Compared with the presample, the mRNA level of the previously reported exercise-induced HSP72 was induced during recovery in exercised subjects. HSP72 mRNA also increased in control subjects but had a different pattern of expression. mRNA levels for the three small heat shock proteins (ß-crystallin, HSP27, and HSP22) were not increased in exercised subjects. In nonexercising control subjects, we observed transient increases of ß-crystallin and HSP22.

3. Gene expression patterns of exercise-induced metabolic genes are influenced by dietary status
To investigate the potential influence of the dietary regimen on previously reported exercise-induced genes, we included a number of oxidative and glycolytic metabolic genes in our analysis. When compared with the initial sample, all three gene markers of oxidative metabolism (LPL, CS, and mFABP) were induced during recovery in exercising subjects but not in control subjects. For LPL, no difference was observed between groups. Among glycolytic gene markers, PDK4 expression increased by a similar magnitude in the exercise and control situations, whereas neither GLUT4 nor glycogen phosphorylase was increased in either situation.

CONCLUSIONS AND SIGNIFICANCE

Our results show that some "exercise-induced" genes (i.e., PGC-1 and mFABP) are indeed exercise induced. Other previously assumed exercise-induced genes, such as PDK4, are in fact more responsive to feeding than fasting and exercise. Similarly, MyoD and p21 appear to be responding to a time-dependent signal other than exercise. HSP72 is more responsive to stress stimuli, yet is also responsive to exercise stimuli. As hypothesized, factors other than exercise affect the expression of muscle genes in a standard human exercise experiment (Fig. 3 ). This result demonstrates that presampling alone can influence the interpretation of exercise-induced muscle gene expression.

View larger version (11K): [in this window] [in a new window]   Figure 3. Schematic diagram illustrating how stimuli other than exercise may potentially influence gene expression when based only on a presampling control strategy. Examples of genes are shown that are only induced (PGC-1), not induced (PDK4), induced(HSP72) or partly induced (LPL) by the exercise stimuli.

Results from previous exercise studies should be reevaluated and conclusions reconsidered, taking into account the possible influence of stimuli unrelated to exercise (e.g., dietary status and sampling-induced trauma). Inclusion of a resting control group is probably more important in exercise studies than is currently appreciated. In a broader perspective, a similar problem may exist in other human intervention studies of gene expression and presumably may apply to signal-transduction using presampling.

FOOTNOTES

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-2084fje;

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