"It never gets easier, you just go faster." - Greg Lemond

Tuesday, July 19, 2011

Enhancing Fatty Acid Oxidation in Skeletal Muscle

PPAR attention to this!

In this blog I hope to discuss training practices used by athletes in order to maximize the results seen from hours upon hours of aerobic training.  Both running and cycling coaches often suggest occasionally training in the fasted state to their athletes.  Also, several nutrition companies suggest very small meals or skipping breakfast on race day in order to maximize fatty acid oxidation during endurance racing.  Thus my goal is to discuss the reliability of these suggestions, as well as propose an exciting potential mechanism.
During endurance exercise contracting muscle fibers rely on a mixture of metabolic substrates to provide energy.  Different types of muscle fibers rely more heavily on different fuel sources.  Glucose serves as the preferred energy source in type IIa (fast twitch) muscle fibers, while type I (slow twitch) muscle fibers rely more heavily on lipid metabolism (1).  Submaximal endurance exercise in particular recruits mostly type I fibers, indicating that there is the potential to rely on fatty acid oxidation as an energy source for endurance sports (2).  Intramyocellular triacylglycol (IMTG), lipoprotein-derived triacylglycerol (TG) and plasma free fatty acids (FFA) are proposed to be the source of lipids oxidized by type I fibers (3).  Indeed, trained athletes accumulate IMTG and rely more heavily on fatty acids to provide energy if exercise is performed in the fasted state, rather than the postprandial state (1, 4). 
Training in the fasted or glycogen depleted state has the potential to alter the metabolic machinery within type I muscle fibers.  Several studies indicate that consistent training in a glycogen depleted state generally results in increased capacity of muscles to oxidize fatty acids through changes in enzyme activity, fatty acid transporter proteins, and gene expression resulting in increased fatty acid oxidation by mitochondria (1, 5).  Interestingly, athletes utilizing carbohydrate depletion training methods also show improved ability to resynthesize muscle glycogen post-exercise (1).  The implications to athletes are substantial, considering that this training may also facilitate glycogen sparing when carbohydrates are consumed during a race (6).  Thus not only would an athlete start a race with optimal muscle glycogen content, but also be able to protect these stores until race conditions demand their use, such as a sprint finish.
Perhaps the most interesting studies examining the impact of increased fatty acid oxidation capacity on endurance exercise were performed using transgenic mice expressing a constitutively active form of the nuclear transcription factor peroxisome proliferation-activated receptor (PPAR) δ.  These mice have been affectionately named “marathon mice” due to the fact that they are able to run twice as far and twice as long as their wild type littermates (7).  PPARδ, also known as PPARβ, is the least studied of the PPAR isoforms, but is the predominate isoform expressed in muscle tissue and its expression is thought to be linked to increased capacity to oxidize fatty acids by mitochondria (7, 8).  Most highly expressed in type I muscle tissue, targeted overexpression of this transcription factor in muscle leads to muscle fibers switching to a type I phenotype.  Furthermore, treatment of wild type mice with a PPARδ agonist induces changes in gene expression similar to targeted overexpression of an active form of the transcription factor (8). 
Endurance training as well as fasting has also been shown to upregulate PPARδ expression and in both mice and humans, resulting in increased capacity to metabolize fatty acids by skeletal muscle (7).  This interesting PPAR provides at least one potential target to increase endurance capacity in both amateur and elite athletes as well as in individuals suffering from metabolic syndrome.  PPARα and PPARγ agonsists are already used in the treatment of hyperlipidemia as well as insulin resistance, respectively.  Interestingly, “marathon mice” are protected from high-fat-diet induced obesity and exhibit improved glucose tolerance compared to wild type controls.  Because of the ability of PPARδ to induce a type I muscle fiber phenotype and enhance skeletal muscle fatty acid oxidation, pharmacological activators have the potential to be an “exercise pill” that can enhance beneficial metabolic gains acknowledged to be a result of endurance training.

Works Cited

1.         De Bock K, Richter EA, Russell AP, Eijnde BO, Derave W, Ramaekers M, Koninckx E, Leger B, Verhaeghe J, Hespel P. Exercise in the fasted state facilitates fibre type-specific intramyocellular lipid breakdown and stimulates glycogen resynthesis in humans. J Physiol. 2005 Apr 15;564:649-60.
2.         van Loon LJ, Greenhaff PL, Constantin-Teodosiu D, Saris WH, Wagenmakers AJ. The effects of increasing exercise intensity on muscle fuel utilisation in humans. J Physiol. 2001 Oct 1;536:295-304.
3.         van Loon LJ, Koopman R, Stegen JH, Wagenmakers AJ, Keizer HA, Saris WH. Intramyocellular lipids form an important substrate source during moderate intensity exercise in endurance-trained males in a fasted state. J Physiol. 2003 Dec 1;553:611-25.
4.         van Loon LJ, Koopman R, Manders R, van der Weegen W, van Kranenburg GP, Keizer HA. Intramyocellular lipid content in type 2 diabetes patients compared with overweight sedentary men and highly trained endurance athletes. Am J Physiol Endocrinol Metab. 2004 Sep;287:E558-65.
5.         Van Proeyen K, Szlufcik K, Nielens H, Ramaekers M, Hespel P. Beneficial metabolic adaptations due to endurance exercise training in the fasted state. J Appl Physiol.  Jan;110:236-45.
6.         De Bock K, Derave W, Eijnde BO, Hesselink MK, Koninckx E, Rose AJ, Schrauwen P, Bonen A, Richter EA, Hespel P. Effect of training in the fasted state on metabolic responses during exercise with carbohydrate intake. J Appl Physiol. 2008 Apr;104:1045-55.
7.         Ehrenborg E, Krook A. Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor delta. Pharmacol Rev. 2009 Sep;61:373-93.
8.         Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham J, Kang H, Evans RM. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol. 2004 Oct;2:e294.


  1. What qualifies as "fasted state"?

    Does this article agree with the information you discuss in this blog entry?:

  2. Hi. IMHO, the fasted state = no food at least 3 hours before the run. preferably, nothing since the night before (if on a morning run). This article agrees that you can train your fat metabolism and that eating immediately before or during a run can diminish the gains in fat burning one would experience. I still am debating whether one would be better served running fasted for as long as they can, then eating a gel or two in order to increase the total span of the run instead of cutting it short due to low energy. Hope this helps.