What Determines the Training Response?

RNA transcription

Isoforms of the transcriptional coactivator PGC-1a determine the response to resistance training and endurance training. The PGC-1a4 isoform causes hypertrophy (an increase in muscle mass) in response to resistance training. In response to endurance training, the PGC-1a1 isoform causes  mitochondrial biogenesis and increases fatty acid oxidation. Transcriptional activators influence gene expression (image to the right) by recruiting RNA polymerase and transcriptional factors.

Resistance training and endurance training cause visibly different effects on muscle tissue. Lifting weights, a typical example of resistance training, results in enlargement of the muscles, called hypertrophy. On the other hand cycling, an endurance activity, increases mitochondrial density in muscle, but does not generally enlarge the muscle.  Endurance training relies on improvement in the cardiovascular system for a good portion of its effected increase in VO2 Max. The answer to why endurance training and resistance training lead to such different effects in muscle fibers can be found in an exciting study recently published in Cell (A PGC-1alpha Isoform Induced by Resistance training Regulates Skeletal Muscle Hypertrophy, 2012. Ruas JL, et al.).

According to this paper, the answer is centered around the molecule PGC-1alpha. Over the past several years PGC-1alpha has generated excitement in the biomedical community for its influence across a wide variety of avenues, several of which have been discussed on this blog: PGc-1alpha reduces muscle wasting in ALS mice models, correlates with the reduction in muscle mass in cigarette smoking mice models, mediates fiber-type switching to type I fibers and is responsible for triggering brown fat production. PGC-1alpha is thought to be responsible for many of the adaptive changes in the muscle to endurance training. The transcriptional coactivator causes mitochondrial biogenesis (increase in mitochondria density results in an increase in aerobic energy production), angiogenesis (increase in blood capillaries within the muscle) and fatty acid oxidation (using fat for energy prolongs complete depletion of vital glycogen stores in the muscle). However, none of these aforementioned effects would increase anaerobic performance.

The authors found PGC-1alpha has four different isozymes through an alternate promoter (a gene promoter is where mRNA transcription machinery binds to the DNA) and alternate splicing (cutting up and piecing together the mRNA stand produced from the gene). They are named PGC-1alpha1, PGC-1alpha2, PGC-1alpha3 and PGC-1alpha4. PGC-1alpha1 is the isoform first discovered and was formerly known as simply PGC-1alpha. Of interest to the researchers was PGC-1alpha4 because it was found to increase Insulin Growth Factor-1 (IGF-1). IGF-1 has been found to induce hypertrophy. Because it increases muscle mass, IGF-1 has gained notoriety as a performance enhancing drug. In addition to increasing IGF-1 expression, PGC-1alpha4 was also found to decrease expression of myostatin, a potent negative regulator of muscle size. PGC-1alpha4 apparently accomplishes this by altering the chromatin structure of the IGF-1 and myostatin genes to respectively increase and decrease gene expression. A model of the PGC-1alpha isomers' exercise-mediated effects on the muscle is shown below.

A model for how exercise via resistance training or endurance training causes an adaptive response through PGC-1alpha

The researchers measured the levels of PGC-alpha1 and PGC-alpha4 in humans.  Muscle biopsies were taken out of humans before and after an endurance training protocol, resistance training protocol and both resistance training and endurance training protocol.  It was found that the combination of endurance and resistance training led to the greatest increase in PGC-1alpha1 and PGC-1alpha4.  All training protocols increased PGC-alpha1.  Although the endurance training protocol did not increase PGC-1alpha4 in the human muscle biopsies, resistance training alone and both resistance and endurance training did increase PGC-alpha4 1.5 fold and 3 fold, respectively.

In mice, PGC-1alpha4 was found to cause hypertrophy relative to a GFP control.  The increase in muscle mass was accompanied by increased force production in the muscle.  In addition, muscle wasting was decreased in PGC-1alpha4 expressing mice during muscle disuse caused by hindlimb suspension. In addition, cachexia (severe muscle weakening) brought about by tumors introduced in muscle tissue was significantly curtailed in PGC-1alpha4 transgenic mice. The figure below demonstrates the PGC-1alpha4 induced muscle hypertrophy in mice gastrocnemius muscle cross sections.

PGC-1alpa4 causes hypertrophy.  This image shows a PGC-1alpha4 mediated increase in muscle cross sectional area.

PGC-1alpha4 has the potential to be a centerpiece of muscle therapy. Because PGC-1alpha4 modulates both IGF-1 and myostatin, it could in theory be used in place of IGF-1 and myostatin regulatory drugs currently in the pharmaceutical pipeline. Furthermore, PGC-1alpha4's potent effects on muscle hypertrophy and muscle force make it a practical marker of the effectiveness of a resistance training program. A resistance training program optimized for increasing muscle mass and force would generate a maximal rise in PGC-1alpha4 expression.  

A future direction with this research is to determine the molecules that lead to transcription at the alternate PGC-1alpha gene promoter and cause alternate splicing to generate the four PGC-1alpha isoforms.

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