Continued from last week
How the hell do I turn this Gene Off?
Besides taking a black market pharamceuatical grade myostatin inhibitor, GH might be a potential inhibitor of myostatin production. Here is another one of those catch-22 studies; I am beginning to believe that any study with GH causes controversy! In GH-deficient males, administration of GH (5 µg/kg per day) resulted in a significant inhibition (~31%) of myostatin muscle mRNA compared to the control group (11). Surprisingly, systemic administration of neither GH nor testosterone to healthy elderly males resulted in no change in myostatin expression; however a combination of both GH and testosterone almost reached a significant effect (12). In a 2001 study, 27 healthy men (>65 years of age) had muscle biopsies and blood samples taken to determine if there was any correlation between GH, testosterone, IGF-1 with mRNA myostatin expression. Results of the study showed there were no significant relationships between age, lean body mass, or percent body fat and transcript levels of growth hormone receptors, IGF-I, androgen receptor, or myostatin. Moreover, there were no significant correlations of serum GH, IGF-I, or T with their corresponding target mRNA levels (GHR, intramuscular IGF-I, or AR) in skeletal muscle. There was a negative relationship between the amount of mRNA muscle myostatin expressed in muscle and GH receptor gene expression (27). There is a documented rise in serum myostatin levels with aging. The author hypothesized since there is a significant downregulation of the GH axis with aging that possibly the decrease in GH may lead to increased myostatin gene expression. GH may be able to downregulate myostatin expression, but more research needs to be conducted. There is controversy as to whether heavy resistance exercise seems to lead to decreases or increases in myostatin gene expression. As mentioned previously, Willboughby (33) reported that when 22 young untrained men performed a 12 week resistance training program at the end of 12 weeks there was an increase in myostatin mRNA gene expression. Contrary to these results, another study found that when untrained young and old men and women were subjected to 9-week heavy resistance training routine, a ~37% decrease in myostatin gene expression was observed in all subjects (16). Interestingly, there were no gender differences between males and females with myostatin expression, one would suspect that testosterone would have some kind of impact on myostatin, but as mentioned in an earlier study administration of testosterone to date has no effect on myostatin production (12). There is something really interesting about resistance exercise effects on myostatin, as mentioned earlier hind limb suspension in mice will cause an increase in myostatin mRNA expression. After 10 days of muscle unloading in mice, there was a 110% increase in myostatin mRNA in muscle however, hind limb unloading combined with intermittent bouts of muscle loading (i.e. 30 minutes on a treadmill with a 20% grade) causes a significant rise in myostatin (~55% increase) but no significant muscle mass loss (18). Results of the study implicate that myostatin expression can be increased during modified muscle load yet not cause significant decreases in muscle mass. I know…I am confused as hell too, but that’s research for you!! I know what you are thinking; I can take a myostatin inhibitor supplement. Well sure, maybe if you stack it with some Boron you will become extra huge!!! A research group in the Exercise and Biochemical Nutrition laboratory at Baylor University did us all bodybuilders a favor and buried that notion. The study examined 12 weeks of resistance training and cystoseira canariensis supplementation (i.e. supplement that is supposed to bind to myostatin) on serum levels of myostatin and muscle strength and body composition. After 12 weeks of heavy resistance training and 1200 mg/d of cystoseira canariensis supplementation there was no difference between the control group and the resistance training group in terms of muscle strength, fat loss, or changes in lean muscle mass. Sorry…don’t shoot the messenger!!
Myostatin and its Regulation on Adipose Tissue
Only a small quantity of myostatin is expressed in adipose tissue compared to muscle, but it seems to have some rather potent effects of regulating adipose tissue size. When myostatin deficient mice were compared to there normal mice counterparts some interesting features were discovered. For up to 2 months of age there were no differences in the amount of fat between the two groups but by 6 months of age there were. After six months of age, the normal mice had fat pads (i.e. lumps of fat) that were 2.4- 4 times greater than that of the myostatin deficient mouse. After 9 months, the normal mice had fat pads nine-fold greater than that of myostatin deficient mice. Here is what is really interesting, so myostatin deficient mice are aging and staying lean, they have normal food intake and normal body temperatures, but have a slightly lower metabolic rate (myostatin deficient mice had lower rates of total oxygen and resting oxygen when expressed as a percentage of bodyweight) (15). So what about humans, I am not a mouse with a myostatin deficiency!! In obese subjects that underwent an operation called a billiopancreatic diversion (a form of gastric bypass surgery in which portions of the stomach are removed) there was a significant decrease in myostatin expression mRNA after weight loss. Also of interest is the possibility of using myostatin to help treat diabetes as an increase in bodyfat increases the risk of diabetes. It is hypothesized that myostatin might reduce the incidence of diabetes by reducing the amount of fatty acids that accumulate in the beta cells of the pancreas which cause insulin release. So far, treatment with myostatin looks promising as mice experimentation with myostatin inhibitors reduced obesity as well as type II diabetes symptoms.
Myostatin, Aging, and Wasting Disease
Aging is associated with a reduction in lean muscle mass with a concomitant increase in fat mass. This partly may be related to the decline in circulating levels of anabolic hormones that might be affecting gene transcription. It is widely believed that thousands of genes and their products (i.e., RNA and proteins) function in a complicated and orchestrated way that creates the mystery of life. However, traditional methods in molecular biology generally work on a “one gene in one experiment” basis, which means that the there is a very limited view of the “whole picture” of gene function. In the past several years, a new technology, called DNA microarray, has attracted tremendous interests among biologists. This technology promises to monitor the whole genome on a single chip so that researchers can have a better picture of the interactions among thousands of genes simultaneously. It’s interesting to see that there are marked differences in gene expression in muscle between older and younger men. When comparing gene expression from biopsies of younger and older men, older muscle had reduced expression of genes involved in energy metabolism (i.e. electron chain transport, ATP synthesis) and increased expression of genes involved in oxidative stress and inflammation. Also reported, the gene with the greatest expression in older men was follistatin, which binds myostatin and inhibits its activity. The author hypothesized that increased follistatin expression may be unregulated to compensate for increased serum levels of myostatin that occurs with aging (28). Elevated serum levels of myostatin not only occur with aging but in many catabolic disease states. The serum concentrations of myostatin have been found to be higher in HIV-infected men than in healthy men; furthermore, myostatin levels are even higher in men who meet the definition of AIDS wasting syndrome (29). When healthy mice are systemically administered myostatin, they develop muscle wasting and fat loss just like many human cachexia syndromes (i.e. wasting diseases). In conclusion, myostatin is a muscle specific protein that negatively regulates muscle mass. Based on the research, increases in myostatin accompany muscle atrophy; significant increases in myostatin do not necessarily produce muscle atrophy. There is growing evidence that adaptation to exercise is not mediated by one signal transduction pathway or mechanism but by several transcription factors binding to enhancers or silencers. Myostatin antagonists seem to be a therapeutic means to alleviating sarcopenia, muscle atrophy, and other wasting diseases. Muscular Dystrophy is documented by extensive muscle inflammation, muscle injury, and replacement of muscle tissue with connective tissue and fat. Researchers have long sought to find agents that block the molecular pathway to Muscular Dystrophy by using “booster genes” to support muscle growth and cope with the otherwise damaging steps leading to Muscular Dystrophy. There are some potential benefits to using myostatin inhibitors as one study showed when a strain of mice who are myostatin deficient mice yet also contain the muscular dystrophy gene have increased muscle mass and increased muscle strength, yet there is still no reduction in inflammation or tissue injury (21). The safety issues of myostatin are still being investigated. It has been suggested by researchers that since myostatin inhibitors cause’s dramatic increases in muscle mass (~20-40 %) can human bone withstand such a dramatic increase in muscle mass in such a short period of time? This probably would not be a problem for a healthy person, but what about a frail elderly person. Finally, myostatin is expressed in the heart as well. The suppression of myostatin could possibly lead in cardiac enlargement. Furthermore, following a heart attack, myostatin expression is upregulated in the heart surrounding the damaged area. It should be mentioned that myostatin deficient mice seem to be healthy although more long term research needs to be conducted.
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