Research Update #14

by Hypertrophy

As we approach the new millennium we find the science of building muscle progressing faster than ever before. Long gone are the days of simple trial and error when it comes to building muscle. The modern bodybuilder demands more than just "hear say" if they are to adopt a new training routine or nutritional supplement. This column was created to keep today’s bodybuilder on the cutting edge of scientific research that might benefit them in their quest for body perfection.

New study shows mixed drinks and muscle growth just don’t mix.

Title: Inhibition of muscle protein synthesis by alcohol is associated with modulation of eIF2B and eIF4E

Researchers: Lang, Charles H., Wu D., Frost RA., Jefferson LS., Kimball SR., and Vary TC.

Departments of Cellular and Molecular Physiology and Surgery, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033

Source: American Journal of Physiology 277 (Endocrinol. Metab. 40): E268–E276, 1999.

The present study examined potential mechanisms for the inhibition of protein synthesis in skeletal muscle after chronic alcohol consumption. Rats were maintained on an alcohol-containing diet for 14 wk; control animals were pair fed. Alcohol-induced myopathy was confirmed by a reduction in lean body mass as well as a decrease in the weight of the gastrocnemius and psoas muscles normalized for tibial length. No alcohol-induced decrease in total RNA content (an estimate of ribosomal RNA) was detected in any muscle examined, suggesting that alcohol reduced translational efficiency but not the capacity for protein synthesis. To identify mechanisms responsible for regulating translational efficiency, we analyzed several eukaryotic initiation factors (eIF). There was no difference in the muscle content of either total eIF2a or the amount of eIF2a in the phosphorylated form between alcohol-fed and control rats. Similarly, the relative amount of eIF2Be in muscle was also not different. In contrast, alcohol decreased eIF2B activity in psoas (fast-twitch) but not in soleus or heart (slow-twitch) muscles. Alcohol feeding also dramatically influenced the distribution of eIF4E in the gastrocnemius (fast-twitch) muscle. Compared with control values, muscle from alcohol-fed rats demonstrated 1) an increased binding of the translational repressor 4E-binding protein 1 (4E-BP1) with eIF4E, 2) a decrease in the phosphorylated g-form of 4E-BP1, and 3) a decrease in eIF4G associated with eIF4E. In summary, these data suggest that chronic alcohol consumption impairs translation initiation in muscle by altering multiple regulatory sites, including eIF2B activity and eIF4E availability.

By analyzing the complex series of steps by which our muscle cells build new proteins we realize that there are many stages in this process where protein synthesis could be modulated. For a more detailed treatment of the steps involved in protein synthesis please refer to November 1, 1998 installment of Research Update in Mesomorphosis Volume 1, Number 7.

From the study above we see that it is translation inhibition that is responsible for the decline in protein synthesis rates seen with alcohol use. This is similar to the mechanism by which exercise inhibits protein synthesis during your workout. Initiation of translation (the binding of mRNA to the ribosomal pre-initiation complex) requires group 4 eukaryotic initiation factors (eIFs). These initiation factors interact with the mRNA in such a way that makes translation (the construction of new proteins from the mRNA strand) possible. Two eIFs, called eIF4A and eIF4B, act in concert to unwind the mRNA strand. Another one called eIF4E binds to what is called the "cap region" and is important for controlling which mRNA strands are translated and also for stabilization of the mRNA strand. Finally, eIF4G is a large polypeptide that acts as a scaffold or framework around which all of these initiation factors and the mRNA and ribosome can be kept in place and proper orientation for translation.

Now it is eIF4E that appears to be a key point for modulation of translation, or protein synthesis. eIF4E (at the mRNA cap) binds with eIf4G (scaffold) in order to form the functional complex (eIF4F) that allows translation of the mRNA. Some research shows that eIF4E activity is modulated by increased phosphorylation of the eIF4E molecule, which in turn increases its binding affinity for the mRNA cap region. This would effectively increase the amount of translation going on and ultimately the amount of protein synthesis. Another explanation involves a "binding protein" called 4E-BP1. It binds the eIF4E molecule making it unable to bind to eIF4G. This effectively would put a stop to the whole process. In the study above it was shown that alcohol increases the binding of 4E-BP1 to eIF4E. Alcohol was also shown to decrease the phosphorylated g-form of 4E-BP1, and decrease the concentration of eIF4G associated with eIF4E. All of this adds up to an inhibition of muscle growth and even an increase in muscle protein breakdown.

Bodybuilders are known to go to great lengths to ensure maximal rates of muscle growth, sometimes even engaging in absurd or even dangerous drug regimens. If they are willing to go to so much trouble, I don’t understand why some still engage in frequent and substantial alcohol consumption. Perhaps it has to do with their personalities. Either way, drinking and muscle growth simply do not mix. You may argue that a drink now and then will not make a difference. I could argue that an extra set or a second scoop of protein won’t make much difference either but I’m sure you wouldn’t hesitate to take those steps to ensure maximum gains. Even though an occasional drink may not throw your gains completely down the crapper, as long as the alcohol is in your system you are NOT growing. Sometimes going the extra mile to do everything you can to be successful gives you that tiny edge over your competitors who were more laxed in the preparations.

Exercise and Diabetes: Long held views of how exercise effects glucose uptake give way to more correct thinking.

Title: Effect of tension on contraction-induced glucose transport in rat skeletal muscle

Researchers: Jacob Ihlemann, Thorkil Ploug, Ylva Hellsten, and Henrik Galbo

Copenhagen Muscle Research Center, Rigshospitalet, and Department of Medical Physiology, The Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark

Source: Am J Physiol Endocrinol Metab 277(2):E208-E214

These researchers questioned the general view that contraction-induced muscle glucose transport only depends on stimulation frequency and not on workload. Incubated soleus muscles were electrically stimulated at a given pattern for 5 min. Resting length was adjusted to achieve either no force (0% P), maximum force (100% P), or 50% of maximum force (50% P). Glucose transport (2-deoxy-D-glucose uptake) increased directly with force development [27 ± 2 (basal), 45 ± 2 (0% P), 68 ± 3 (50% P), and 94 ± 3 (100% P) nmol × g1 × 5 min1]. Glycogen decreased at 0% P but did not change further with force development. Lactate, AMP, and IMP concentrations were higher and ATP concentrations lower when force was produced than when it was not. 5'-AMP-activated protein kinase (AMPK) activity increased directly with force [20 ± 2 (basal), 60 ± 11 (0% P), 91 ± 12 (50% P), and 109 ± 12 (100% P) pmol × mg1 × min1]. Passive stretch (~86% P) doubled glucose transport without altering metabolism. In conclusion, contraction-induced muscle glucose transport varies directly with force development and is not solely determined by stimulation frequency. AMPK activity is probably an essential determinant of contraction-induced glucose transport. In contrast, glycogen concentrations per se do not play a major role. Finally, passive stretch per se increases glucose transport in muscle.

Exercise can serve as a powerful tool in the management of diabetes. Physical activity in the form of a structured exercise program can have a pronounced effect on carbohydrate metabolism as well as lipid metabolism. It can also have beneficial effects on disorders associated with diabetes such as obesity, dyslipoproteinaemia, and high blood pressure. Exercise, by helping to regulate blood glucose levels, my also serve to postpone the onset of disorders associated with microvascular disease such as neuropathy, nephropathy, and retinopathy. Thus a structured exercise program has the potential to be a valuable tool in the management of diabetes.

Several studies have shown the beneficial effects of exercise on glycemic control in diabetics. This effect appears to be the result of mechanical and/or metabolic activity of exercising muscle tissue. During, and for a short period after, an acute bout of exercise of moderate intensity, glucose uptake is enhanced in skeletal muscle. This is referred to as non-insulin dependant glucose up take. Muscle contractions and insulin cause the translocation of the GLUT4 glucose transporter proteins to the plasma membrane and transverse tubules. The subcellular origin of the GLUT4-containing vesicles is not clear, but exercise and insulin appear to recruit distinct GLUT4-containing vesicles, and/or mobilize different pools of GLUT4 proteins. Insulin-stimulated GLUT4 translocation involves IRS-1 and PI 3-kinase, and the redistribution of Rab4 (a molecule specific to insulin stimulated GLUT4 translocation). Exercising muscle utilizes a phosphatidylinositol 3-kinase and MAP kinase-independent mechanism and does not result in the redistribution of Rab4. It has been thought that the contraction signal is probably initiated by the release of calcium from the sarcoplasmic reticulum and may involve and autocrine/paracrine mechanism (e.g. nitric oxide, adenosine, bradykinin), protein kinase C, or a combination of these and other currently unknown factors.

The study we look at today shows us some very important things about what is responsible for the increase in glucose uptake by skeletal muscle following exercise. The major findings are that at a given frequency of contractions glucose transport varies directly with developed force. For decades it has been believed that contraction-induced glucose transport is determined only by the frequency with which muscle is stimulated and not by mechanical loading. You will see evidence of this belief in the current protocols used for treatment of diabetics with high volume, low intensity endurance exercise.

It has been observed previously that glycogen content and glucose uptake are inversely related. It is believed that glucose transporters are liberated from the golgi vesicles in response to the breakdown of glycogen molecules. In the present study there were no significant differences in glycogen levels between groups, however, glucose transport was 300% greater despite equal glycogen stores, in the high tension group.

Finally, an interesting finding was that passive stretch also caused an increase in glucose uptake. It is known that intracellular Ca+ concentrations have an effect on glucose transport. It was thought that sarcolemmal damage may have caused calcium ions to flood the intracellular space giving rise to increased glucose transport. This tuned out not to be the case. The ability of simply stretching a muscle to cause glucose uptake remains to be explained.

The results of this study along with other recent research showing resistance exercise to in fact be superior for increasing muscle glucose uptake needs to be considered when prescribing exercise for diabetic patients. This information should also be useful to diabetics who currently enjoy bodybuilding or other strength sports.

Have doctors been exaggerating the effect of steroids on your liver?

Title: Anabolic steroid-induced hepatotoxicity: is it overstated?

Researchers: Dickerman RD, Pertusi RM, Zachariah NY, Dufour DR, McConathy WJ

The Department of Biomedical Science, University of North Texas Health Science Center, Fort Worth 76107-2699, USA.

Source: Clin J Sport Med 1999 Jan;9(1):34-9

Subjects: The participants were bodybuilders taking self-directed regimens of anabolic steroids (n = 15) and bodybuilders not taking steroids (n = 10). Blood chemistry profiles from patients with viral hepatitis (n = 49) and exercising and non-exercising medical students (592) were used as controls.

Measurements: The focus of the blood chemistry profiles was on aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltranspeptidase (GGT), and creatine kinase (CK) levels. (All indicators of liver function.)

Results: In both groups of bodybuilders, CK, AST, and ALT were elevated, whereas GGT remained in the normal range. In contrast, patients with hepatitis had elevations of all three enzymes: ALT, AST, and GGT. Creatine kinase (CK) was elevated in all exercising groups. Patients with hepatitis were the only group in which a correlation was found between aminotransferases and GGT.

Discussion:

All in all this study was pretty straight forward. It set out to see if markers other than aminotransferase (AST) of liver function were correlated with steroid use in bodybuilders. In this study we saw the comparison of blood samples from steroid using bodybuilders, non-steroid using bodybuilders, med students, and patients with hepatitis. Several indicators of liver function were measured wich included aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltranspeptidase (GGT), and creatine kinase (CK) levels. Creatine kinase is a common blood marker of muscle damage and thus it was elevated in those subjects who exercised. The other markers have normal values as well in healthy subjects (see table 1). I include a table of normal ranges for these markers simply to give you some idea of what your particular blood test results mean if you should have them done while on a cycle. And yes, if you are lucky enough to have a doctor who is willing to monitor your health knowing you are using anabolics please have your blood work done before, during, and after your cycles.

Table 1.

Please don’t misinterpret the reason for my inclusion of this study in Research Update. I am by no stretch of the imagination claiming that this study proves that 17-a-alkylated steroids are not hard on the liver. On the contrary, extremely high doses of 17-alkylated androgens taken for extended periods of time have been known to produce signs of hepatic adenomas, hepatocellular carcinomas, and hepatis-peliosis, all of which can be serious problems. The reason I felt this study warranted mention was that it showed that some researchers are working hard to delineate or clarify the true effects , and side effects, of anabolic steroid use in bodybuilders. In particular, R Dickerman and colleagues over at the Department of Biomedical Science, University of North Texas Health Science Center have recently done several studies investigating the effects of anabolic steroids on various aspects of physiology.

To summarize, the usual tests that have been relied on to declare hepatotoxicity from steroid use may be and are very likely to be, inadequate to justify such a claim when considering the type of subjects in this study. The lack of abnormality in gamma-glutamyltranspeptidase from bodybuilders using anabolics indicates that the elevated levels of the other markers may be misleading when it comes to true liver function and may be partly related to muscle damaged induced by resistance exercise. The authors of this study put it this way: 

"Prior reports of anabolic steroid-induced hepatotoxicity based on elevated aminotransferase levels may have been overstated, because no exercising subjects, including steroid users, demonstrated hepatic dysfunction based on GGT levels. Such reports may have misled the medical community to emphasize steroid-induced hepatotoxicity when interpreting elevated aminotransferase levels and disregard muscle damage. For these reasons, when evaluating hepatic function in cases of anabolic steroid therapy or abuse, CK and GGT levels should be considered in addition to ALT and AST levels as essential elements of the assessment."

This is not a statement giving the green light to bodybuilders who are or who intend to use androgens. It is simply a logical and interesting conclusion based on this study’s results. As usual, always educate yourself as to the risks involved with androgen use and take the necessary steps and precautions to minimize those risks if you plan on using them.