Carbohydrate Availability and Training Adaptation: Effects on Cell Metabolism

John A. Hawley; Louise M. Burke

Disclosures

Exerc Sport Sci Rev. 2010;38(4):152-160. 

In This Article

Potential Mechanisms Underlying Augmented Training Adaptation with Low Carbohydrate Availability

To date, the balance of evidence demonstrates that commencing a portion of short-term endurance-based training programs in the face of low carbohydrate availability promotes training adaptation (i.e., mitochondrial biogenesis) to a greater extent than when subjects undertake similar training regimens with high carbohydrate availability. Certainly, in all of the studies reviewed, there is no evidence of impaired adaptation or even a decrement to any performance outcome with low carbohydrate availability. So what are some of the potential mechanisms that underlie this amplified adaptive process when both previously untrained subjects and well-trained athletes deliberately commence selected training sessions with low endogenous and/or exogenous carbohydrate availability?

There are several putative exercise and/or nutrient-induced signaling pathways that promote mitochondrial biogenesis in skeletal muscle. The initial breakthrough in understanding how repeated contractions (i.e., exercise training) promoted mitochondrial biogenesis was the discovery of the transcription factors that regulate expression of the nuclear genes that encode mitochondrial proteins. These include nuclear-respiratory factor 1 (NRF-1) and NRF-2, which bind to the promoters and activate transcription of the genes that encode mitochondrial respiratory chain proteins. The second breakthrough was the discovery of an inducible coactivator, PGC-1α, which docks on and activates these transcription factors and thus activates and regulates the coordinated expression of mitochondrial proteins encoded in the nuclear and mitochondrial genomes.[17]

Much interest has focused on elucidating a possible role for the AMPK in promoting many of the contractile-induced adaptations in skeletal muscle, including mitochondrial biogenesis. Given the role of the AMPK in regulating cellular energy metabolism, this is perhaps not surprising: during exercise, the perturbations in cellular energy balance lead to AMPK-induced activation of several metabolic and catabolic pathways that restore energy equilibrium (i.e., match ATP supply to ATP demand). To explore a potential role for the AMPK in training adaptation, we recently investigated acute skeletal muscle signaling responses to a single bout of HIT commenced with low or normal muscle glycogen stores in endurance-trained cyclists/triathletes.[34] Six athletes performed a 100-min ride at ~70% V·O2peak (AT) on day 1 and HIT (8 × 5-min work bouts at maximal self-selected effort with 1-min rest) 24 h later (HIGH), whereas another six subjects (matched for fitness and training history) performed AT on day 1, then, 1 to 2 h later, the HIT session (LOW). Muscle biopsies were taken before and after both AT and HIT. AMPK phosphorylation increased significantly in both cohorts after HIT (P < 0.05), independent of starting muscle glycogen status, but the magnitude of increase was greater in LOW than HIGH (P < 0.05). A possible explanation for the finding of a higher AMPK activation in the face of low muscle glycogen availability is evidence that glycogen binding to the glycogen-binding domain on the AMPK β subunit allosterically inhibits AMPK activity and phosphorylation by upstream kinases.[23] McBride et al.[23] recently reported that AMPK is inhibited by glycogen, particularly preparations with high branching content. Moreover, they also demonstrated that this inhibition of AMPK activation by carbohydrates was largely dependent on the glycogen-binding domain being abolished by mutation of residues required for carbohydrate binding. Collectively, these results strongly suggest that glycogen is a potent regulator of AMPK activity through its association with the glycogen-binding domain on the AMPK β subunit.

Another nutrient-sensitive signaling molecule potentially involved in the altered skeletal muscle adaptive response after training under conditions of restricted carbohydrate availability is the p38 mitogen-activated protein kinase (MAPK). The p38 MAPK phosphorylates and activates PGC-1α and also increases PGC-1α expression by phosphorylating the activating transcription factor 2, which increases PGC-1 protein expression by binding to and activating the CREB site on the PGC-1α promoter. Exercise results in rapid activation of p38 MAPK, which mediates both the activation and increased expression of PGC-1α. To investigate the role of altered carbohydrate availability on the p38 MAPK response in muscle, Cochran et al.[9] had untrained subjects perform two training sessions the same day (a morning and afternoon session both consisting of 5 × 4 min cycling at ~90% of maximal heart rate) separated by 3 h of passive recovery during which subjects ingested either a high-carbohydrate drink or placebo. Biopsies of the vastus lateralis revealed an exercise-induced increase in the phosphorylation of p38 MAPK (~4-fold; P < 0.05) with a return to baseline levels before the second training bout, regardless of nutritional manipulation. However, after the second training session p38 MAPK phosphorylation was higher after the placebo trial compared with when carbohydrate availability was increased (P < 0.05). Further support for the contention that chronic elevation of p38 MAPK signaling may play a role in promoting the greater response-adaptation reported after training with low carbohydrate availability comes from the data of Morton et al.[24] They showed that when individuals increased carbohydrate availability during the second of twice-daily training sessions for 6 wk, the increase in SDH activity was blunted compared with when subjects were carbohydrate restricted between training sessions.[25]

Low Carbohydrate or Increased Fat Availability?

A major problem for the basic scientist when trying to unravel potential mechanism(s) underlying the benefit to training adaptation with reduced carbohydrate availability is the fact that carbohydrate restriction has reciprocal and pronounced effects on lipid availability, (i.e., increased circulating FFA concentrations and/or elevated muscle triacylglycerol levels). Evidence linking the increased p38 MAPK response to low carbohydrate rather than high FFA availability comes from the study of Watt et al.[31] These workers showed that p38 MAPK phosphorylation levels were increased during prolonged (3 h) cycling exercise in humans when circulating FFA levels were artificially suppressed by administration of nicotinic acid. Results from animal studies, however, show that prolonged (4 wk) elevation of FFA promotes mitochondrial biogenesis and the capacity to oxidize fatty acids to a greater extent than chow-fed animals.[14]

Finally, it is important to note that carbohydrate availability is not the only variable manipulated in the investigations reviewed herein. Many of the studies used different training modes (cycling vs running vs one-leg kicking), a different number of training sessions, and variable intervention periods. It is quite possible that some of the results may not be directly attributable to differences in carbohydrate availability per se but rather to the effects of the exercise training protocol itself (i.e., differences in recovery time between workouts, training once a day vs twice every second day).

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