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Editorial Focus
Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Manchester, United Kingdom
BYE AND COLLEAGUES (3) investigate the contribution of the muscle transcriptome to differences in aerobic capacity of rats selected for high running capacity. The high-throughput transcript profiling of soleus muscle before and after 6 wk of endurance training identified impaired expression of distinct sets of genes in low capacity runners. Gene ontology enrichment revealed that the performance deficits in low capacity runners were connected to transcript differences of the trait of oxidative metabolism. The effort of the Norwegian-US collaboration exemplifies how the mastering of state-of-the-art biotechnology and biostatistics can be applied in combination with artificial selection to unravel the molecular mechanism behind alterations in aerobic fitness.
The main strength of the study results from the proficient use of electronic algorithms to classify significant RNA changes into functional categories (ontologies). Distinct elements of the biostatistical and bioinformatic evaluation of Bye and colleagues are worth highlighting in view of possible avenues to maximize the scientific output of high-throughput investigations (5).
Foremost this concerns the low number of biological replicas (n = 4) and the use of a theoretical false discovery rate in the attribution of significance. Due to these limitations the paper falls short of delivering robust messages on small muscle RNA differences between high and low capacity runners. Such adjustments are indicated by differences in composition of muscle tissue between athletically distinct populations and obviously play a role in governing steady-state differences (10). It appears that the inclusion of a reasonable number of independent data sets (>5) is the obvious remedy to overcome this general weakness of omics studies (5). A second point includes the methodology used to normalize muscle RNAs before running the statistics. Differences in concentration of the labile RNA pool are commonly observed when studying (muscle) tissue adaptations (11) and could give rise to a reference bias for the determination of transcript-level changes between strains and interventions (6). In the Bye et al. (3) study this commonly ignored fact was controlled by additional measures demonstrating equal RNA concentration in soleus muscle between low and high capacity runners. The last point relates to limitations in current gene annotation. As evident in Table 3 of this exemplary paper, certain specifications for significantly altered gene ontologies, i.e., GO:0003824 "catalytic activity," do not provide real biological information. Living organisms exist through the perpetuation of energy-dependent reactions. The biostatistical community should be alerted to understand the poor biological content of nonqualifying molecular specifications. This formalistic consideration may be of general relevance for a successful synthesis between the disciplines of systems biology (4). Possibly a more stringent assessment of the given biological context of molecular data would allow the scientific relevance of output generated from high-throughput research to be maximized.
Consultation of the literature supports the importance of the biological examination of information available through digital and analog sources. The subjective mining of the bibliome by the present author points out that the report of Bye and colleagues (3) extends seminal contributions on the conditioning of aerobic metabolism by muscle work to the molecular level. Contractile work during exercise can elevate energy consumption up to 20-fold (18, 25). This causes the depletion of limited energy stores. Continued exercise therefore relies on efficient energy production to prevent metabolic fatigue. Under these conditions energy fueling is essentially matched via an elevation of ATP production through an integrated increase in delivery and aerobic/anaerobic combustion of organic substrates in muscle cells (24). This aerobic pathway involves connected organ systems starting with oxygen uptake in the lung and extending down to the delivery in the cardiovasculature and cellular respiration in peripheral muscle (Fig. 1). Maximal oxygen uptake, VO2max, essentially reflects the functionality of the interconnected organ system that builds this "pathway of oxygen" and is a main indicator of metabolic fitness and morbidity (1). With increased numbers of the population being affected by metabolic dysfunction, this topic has gained importance (2). As interest in this research has intensified, the anecdotal evidence for the role of lifestyle choices has been substantiated. Both regular exercise and diet are now recognized as counteractive measures for the deconditioning of energy metabolism through adaptation of cellular respiration (1, 2, 17).
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The new data of the Norwegian-US collaboration extends this contention to a highly resolved level. Common patterns of gene expression point out an interaction of genetic predisposition for high VO2max and the environmental stimulus of exercise. The specific RNA regulation demonstrates that the inborn level of fitness influences adaptation of the assessed soleus muscle to exercise. These results highlight the power of a high-throughput approach to reveal a global view on the dynamic molecular events underlying muscle's contribution to metabolic performance and health.
The transcriptome profiling in sedentary animals hint that this deficit of the sedentary rats is associated with deregulated muscle expression of a main regulator of translation in mitochondria, leucyl-transfer RNA synthetase, which is related to mitochondrial disorder and diabetes. Wisløff and coworkers (26) have already demonstrated that cardiovascular deficits occur in the rat population selected for low running performance. These observations define a new concept on the contribution of mitochondrial deficiencies to metabolic dysfunction. These conclusions reflect the key role of the mitochondrial powerhouse for energy production and the pathologic influence of mitochondrial mutations for energy metabolism (6a).
Two systemic issues are worth further investigation to consolidate the proposed role on activity-dependent muscle plasticity for aerobic fitness. Firstly, the apparent speed of adaptation after only 11 generations in the studied muscle tissue is puzzling. The soleus muscle under investigation does not represent a major part of the motor mass being recruited for running (12). Rather soleus muscle activity is mainly devoted to postural control. Previous studies into selectable running performance of Mus domesticus identified that the athletic advantage arose through phenotypic adjustments of gastrocnemius muscle, which plays a larger part than soleus in plantar flexion of the foot (8). Future investigations into the gene-mediated control of metabolic fitness would likely profit from the consideration of the main locomotors. Such studies have been performed with knee extensor groups in humans. These investigations delineated that the transcript response of gene ontologies underlying oxidative metabolism is a main response to endurance-type exercise and manifests as steady-state differences after training (23). Importantly, transcript adjustments in muscle match structural-functional adjustments of respiration including mitochondria and VO2max (9). The indication of Bye and colleagues (3) of the manifestation of aberrant gene control after selective breeding between low or high capacity runners compares to the results of the Garland laboratory with similar changes after only 26 cycles of breeding (8). Interestingly, the gene-dependent enhancement of oxidative performance in these evolutionary experiments did not evolve de novo during the selection process. They represented the enrichment of a recessive allele on chromosome 11 that was present at 7% frequency in the founder pair (13). Gene linkage studies are now indicated to resolve whether common dysregulation of mitochondrial biogenesis explains lower running capacity in selected strains of rodents as shown formerly for the master transcriptional regulator HIF-1
in humans (9, 21).
A systematic investigation of gene-environment interactions for the conditioning of the pathway of oxygen could provide a major impetus for novel therapeutic strategies with aim to prevent, rather than simply stabilize deterioration of metabolic fitness. The assessment of training-induced transcript alterations by Bye and colleagues constitutes an important step in this direction. Future studies into this clinical topic will have to consider the complex interaction of body and environmental variables and the notorious variability in human studies.
FOOTNOTES
Address for reprint requests and other correspondence: M. Flück, Inst. for Biomedical Research into Human Movement and Health, Manchester Metropolitan Univ., Oxford Rd., Manchester M15 6BH, UK (e-mail: m.flueck{at}mmu.ac.uk).
REFERENCES
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