Myostatin, IGF-1 and cytokines have all been found to influence muscle mass in both animal and human studies. A new study published in the Journal of Physiological Genomics examined these genes in response to resistance exercise, and the results may shock you.

Hyper-responders, or what we like to call 'those lucky bastards,' are those who have greater than normal increases in muscle mass and strength compared to the rest of the population. Men respond with huge variations in muscle mass and strength changes when put through a resistance exercise protocol.

Muscle size increased from 3 percent to 59 percent and strength increased 0 percent to 250 percent in a large cohort of healthy young adults.1 Many of you will likely say, "They have a myostatin deficiency," or some other genetic mutation that allows them to pack on greater increases in size and strength. How would you like to have a 250 percent increase in muscle mass compared to your friend, who is doing the exact same workout? So what makes a person a hyper-responder to larger increases in muscle mass and strength? It's all in the genes.

Genes and Muscle Hypertrophy

There are many genes that have been implicated in the role of muscle hypertrophy. Here are a few:

Angiotensin-converting enzyme (ACE) contributes to blood flow, blood pressure, vascularity, glycogen storage, and other things. Athletes who have a DD (deletion/deletion) of the ACE gene and have more ACE have poorer endurance-oriented performance, but greater muscular strength and muscular hypertrophy, more type II fibers and more cellular glucose stores. They also appear to have a much greater risk of heart disease, high blood pressure, stroke, and lean toward visceral fat accumulation.2,3 The angiotensin I-converting enzyme influences the response to resistance training and the muscle regulatory factors, which are common targets of muscle hypertrophy for gene expression studies.

Cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, that are released in response to injury, are thought to inhibit growth and cause muscle wasting, at least in part by inhibiting anabolic hormones such as insulin-like growth factor 1 (IGF-1). A recent study including older adults (aged 65-80) showed that compared to younger adults, older adults had higher levels of muscle cytokine transcripts at baseline, and as a group did not display the 72-hour post-exercise induction of cytokines.4 Some cytokine as interleukin-6 has been implicated in enhancing protein synthesis, and the cytokine response to resistance exercise seems to be a necessary part of the muscle hypertrophy process.5

Myostatin, a member of the transforming growth factor superfamily, is perhaps the single-most powerful negative regulator of developmental muscle growth— as demonstrated by marked muscle hypertrophy in myostatin 'knockout' mice.6

The first human study involving a myostatin-lowering serum (MYO-029) enrolled 136 subjects with various forms of muscular dystrophy. In this first-ever study of a myostatin inhibitor, the primary objective was safety. MYO-029 was well tolerated in people with muscular dystrophies. No target-related side effects were identified to skeletal, smooth or cardiac muscle. Muscle mass increased by approximately 2.4 percent in the 3mg/kg cohort; additionally, there was a dose-dependent increase in fiber diameter in the 3-milligram and 10mg/kg groups.

The disappointing result of the study is that the myostatin inhibitor did not produce increases in strength. The myostatin drug seemed to have good tolerability at lower doses, but at higher doses many subjects experienced adverse skin reactions. The most exciting aspect of the study was that there were no adverse effects on the heart.

IGF-1. A number of studies have associated age-related declines in circulating anabolic factors, including IGF-1 and testosterone, with the muscle atrophy of aging— suggesting that these serum factors are important for the maintenance of muscle mass. Furthermore, exogenous IGF-1 applied to atrophied muscles in rats has been shown to significantly increase muscle mass and satellite cell activity.

Which Genes Contribute the Most to Muscle Hypertrophy?

All of the genes mentioned have been previously reported to play a role in muscle hypertrophy, so researchers did something really interesting. They took baselines samples of these genes and had older men (aged 60 and over) complete a single session of acute resistance exercise, followed by a 36-session, progressive, resistance exercise training program. The training program was designed to increase mass and strength for the thigh muscles by exercising three times per week on nonconsecutive days, for 12 weeks.

Subjects rested for 5 minutes and then completed 3 sets of 8 repetitions, followed by a fourth set of repetitions to voluntary failure for each of the three exercises, at 80 percent 1 RM. Subjects were given two minutes rest between each set and five minutes rest between exercises. Subjects were supervised during each session to ensure proper form and safety. 1 RM was determined every two weeks, and the 80 percent of 1 RM workload was readjusted.

Without Good Genes, You're Screwed!

As with younger adults, older adults participating in this study showed a variable range of responses to resistance exercise training, ranging from 1 percent to 18 percent increases in muscle mass and 8 percent to 65 percent increases in muscle strength. Training increased thigh muscle size (7 percent) and strength for the three exercises performed: knee extension (30 percent), leg curl (28 percent) and leg press (20 percent).

Researchers screened 18 predominant genes that play a role in the function of inflammation, growth and muscle remodeling that were previously demonstrated to be regulated by aging and acute exercise. The gain in extension strength and muscle size was high, and significantly, correlated with gene expression. The training outcome in muscle mass and strength correlated with the level of transcripts growth factors at baseline (resting levels).

This means the men who had higher baseline expression of key genes conducive to muscle growth displayed an adaptive advantage to the training routine, compared to other men. Individuals with lower baseline expression of genes conducive for muscle hypertrophy showed less adaptation to exercise, despite increased gene expression in response to training.

Basically, it means if you have poor genes to begin with... you're screwed!

Gene Response: Not What You'd Expect

Researchers made several hypotheses before the study. Some were supported by the study, but some were not. Here are some of the initial hypotheses and the results of the study:

Cytokines

Hypothesis 1: The magnitude of the cytokine response to acute resistance exercise would be predictive of a person's adaptability to the exercise program. For example, those with the highest levels of post-exercise inflammation would have inhibited gains in strength and muscle mass. The claims were NOT SUPPORTED by the study. Changes in neither inflammatory nor anti-inflammatory cytokine expression after acute exercise were related to training outcomes.

Hypothesis 2: Higher baseline levels of pro-inflammatory cytokines such as interleukin-1 would diminish training outcomes. This claim was also NOT SUPPORTED. Much to the researchers' surprise, the opposite relationship occurred— individuals with the highest baseline interleukin-1 levels were correlated with greater strength gains.

Hypothesis 3: Training-induced decrease in interleukin-1 would be related to better training outcomes. This claim WAS SUPPORTED. Individuals who gained the most strength also had the largest decrease in the inflammatory-mediator interleukin-1, after training. Similar results were found for the interleukin-1 receptor antagonist and interleukin-10, suggesting that the anti-inflammatory effect of resistance training that has been seen in other groups is also an important part of adaptation.

IGF-1

The study found that individuals with the lowest IGF-1 and its binding proteins at rest had the worst outcome in strength and muscle mass, whereas those who had higher muscle IGF-1 levels had the best gains in strength and size. This study was similar to previous findings that compared 'responders' and 'non-responders' with respect to muscle hypertrophy. The change in IGF-1 expression 24 hours after acute exercise was significantly related to muscle hypertrophy.7

Myostatin

This was the biggest shocker of the study. The study showed that those with the highest resting levels of myostatin, which is a negative growth factor at baseline, were predictive of those who made the greatest gains in training and also muscle size. WTF? That's exactly what I thought, and the researchers explained that resistance exercise lowers myostatin levels— so it could be that those with the highest levels would have the most suppression of myostatin in response to resistance exercise.

This is not the first study to find that higher levels of myostatin are associated with increased gains in muscle mass. A previous study found similar results, which supports the 'novel paradox' whereby individuals with higher baseline levels of the 'antigrowth factor' myostatin have greater potential for muscle growth.

The current study found that the resistance exercise program caused a decrease in myostatin expression, with exercise. Myostatin downregulation after acute exercise was strongly associated with muscle mass gains after training.8 The researchers also showed that the magnitude of myostatin suppression by training was strongly related to strength gains.

What makes this study so important is that the baseline levels of several genes predicted the degree of muscle hypertrophy and strength, whereas the changes in gene expression after acute exercise were not associated with training outcomes.9

It always has amazed me how some bodybuilders can just transform overnight after a few weeks of heavy training. These results suggest that higher baseline expression for key genes in muscle conveys an adaptive advantage for certain older adults. Individuals with lower baseline expression of these genes show less adaptation to exercise, despite increased gene expression in response to training. These genes hold promise as useful predictors of training outcomes that could be used to design more effective exercise regimens for maintaining muscle function in older adults.

One thing that should be kept in mind— this study was performed using older adults. Younger adults may have an entirely different response. This study is the first to demonstrate that the baseline levels of genes are more important than the training response of genes to resistance exercise.

References:

1. Hubal MJ, Gordish-Dressman H, Thompson PD, Price TB, Hoffman EP, Angelopoulos TJ, Gordon PM, Moyna NM, Pescatello LS, Visich PS, Zoeller RF, Seip RL, Clarkson PM. Variability in muscle size and strength gain after unilateral resistance training. Med Sci Sports Exerc, 37: 964-972, 2005.

2. Effect of angiotensin-converting enzyme insertion/deletion polymorphism DD genotype on high-frequency heart rate variability in African Americans. Thayer, Merritt, Sollers, Zonderman, Evans, Yie, Abernethy. National Institute on Aging Intramural Research Program, the National Center on Minority Health and Health Disparities, National Institutes of Health, Bethesda, Maryland, USA.

3. Elevated mortality rates from circulatory disease in African American men and women of Los Angeles County, California— a possible genetic susceptibility? Henderson, Cotezee, Ross, Yu. Department of Emergency Medicine, University of Southern California School of Medicine, Los Angeles, USA.

4. Przybyla B, Gurley C, Harvey JF, Bearden E, Kortebein P, Evans WJ, Sullivan DH, Peterson CA, Dennis RA. Aging alters macrophage properties in human skeletal muscle both at rest and in response to acute resistance exercise. Exp Gerontol, 41: 320-327, 2006.

5. Hamada K, Vannier E, Sacheck JM, Witsell AL, Roubenoff R. Senescence of human skeletal muscle impairs the local inflammatory cytokine response to acute eccentric exercise. FASEB J, 2005 Feb;19(2):264-6.

6. Benabdallah BF, Bouchentouf M, Tremblay JP. Improved success of myoblast transplantation in mdx mice by blocking the myostatin signal. Transplantation, 2005;79:1696-1702.

7. Bamman MM, Petrella JK, Kim JS, Mayhew DL, Cross JM. Cluster analysis tests the importance of myogenic gene expression during myofiber hypertrophy in humans. J Appl Physiol, 102: 2232–2239, 2007.

8. Hulmi JJ, Ahtiainen JP, Kaasalainen T, Pollanen E, Hakkinen K, Alen M, Selanne H, Kovanen V, Mero AA. Postexercise myostatin and activin IIb mRNA levels: effects of strength training. Med Sci Sports Exerc, 39: 289-297, 2007.

9. Dennis RA, Zhu H, Kortebein PM, Bush HM, Harvey JF, Sullivan DH, Peterson CA. Muscle expression of genes associated with inflammation, growth, and remodeling is strongly correlated in older adults with resistance training outcomes. Physiol Genomics, 2009 Jul 9;38(2):169-75.