Abstract

Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity.

To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity.

Our results demonstrate that Mstn mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes.

Citation: Guo T, Jou W, Chanturiya T, Portas J, Gavrilova O, et al. (2009) Myostatin Inhibition in Muscle, but Not Adipose Tissue, Decreases Fat Mass and Improves Insulin Sensitivity. PLoS ONE 4(3): e4937. doi:10.1371/journal.pone.0004937

Inhibiting a growth factor that keeps muscles from getting too big may optimize recovery of injured soldiers, researchers say. They are studying two myostatin inhibitors in mice with limb injuries, first to see which works best and then to identify the best delivery mechanism, says Dr. Mark Hamrick, one biologist in the Medical College of Georgia Schools of Graduate Studies and Medicine.

“Fifty to 60 percent of the injuries occurring in Iraq are to the limbs, and the average injury requires five surgeries,” Dr. Hamrick says. “Myostatin inhibitors are known to improve muscle regeneration and we have evidence that they also increase bone formation. We believe these inhibitors will result in a stronger, more rapid recovery for these soldiers and other victims of traumatic limb injuries.”

A $1.2 million grant from the Office of Naval Research to Dr. Hamrick is enabling laboratory studies of two experimental myostatin inhibitors: a decoy receptor and a binding protein, both developed by MetaMorphix, Inc. of Beltsville, Md. Both inhibitors have been shown effective in muscle regeneration, but this is the first trial that looks at their impact on bone.

Two delivery mechanisms also will be studied. “Is the best approach a single injection bolus that circulates everywhere or just localized delivery?” Dr. Hamrick says.

Study collaborators include Dr. Li Liang of the life sciences company MetaMorphix, who will oversee development of the inhibitors; Dr. Xuejun Wen, bioengineer at Clemson University in Clemson, S.C.; and David Immel, radiographic imaging expert at Savannah River National Laboratory in Aiken, S.C., who will provide three-dimensional, high-resolution computerized tomography scans of injured limbs before and after treatment.

Myostatin is primarily produced by muscle cells. Females tend to produce more myostatin receptors, which helps explain why men tend to have greater muscle mass. Dr. Hamrick’s lab also has found the receptor on bone-derived stem cells – needed to help repair an injury – and others have found it in healing fractures. “When you take it away, the healed callus that forms at the fracture site has more bone in it,” says Dr. Hamrick. “Myostatin also increases fibrosis and scarring within tissue so part of what you are doing is blocking that.”

Bone and muscle healing typically go hand in hand. Muscle provides blood, growth factors and potentially stem cells for a healing callus. It’s not yet known how well bones reciprocate. “If you can improve muscle healing, you can improve bone healing,” Dr. Hamrick says. “Young people have a tremendous potential to heal that can be improved with better approaches to preventing infection and to healing soft tissue and bone in an integrated manner.”

Researchers hope to move to clinical trials in two to three years, Dr. Hamrick says. “If we find the primary role of myostatin is very early in the healing process and see a big jump in expression early in a fracture callus, it may be that a single injection bolus immediately after injury is the best time for treatment rather than continued treatment over a period of time.”

Myostatin is most highly expressed during development, but adults have some as well, so blocking it still facilitates muscle growth and development, primarily in response to exercise. Myostatin expression also tends to rise following an injury, apparently to control proliferation of new and regenerating cells, Dr. Hamrick says. Although there is no FDA-approved myostatin inhibitor, body builders often take supplements that claim to reduce myostatin function and help build muscle.

A whole spectrum of naturally occurring genetic variations likely result in minor alterations in myostatin signaling that could help explain why some people are more muscular than others, Dr. Hamrick notes. In a separate study funded by the National Institutes of Health, he is using a genetically engineered ‘mighty mouse,’ which is missing the myostatin gene, to find the best way to optimize bone growth and help young people avoid osteoporosis. German researchers reported in 2004 in the New England Journal of Medicine the case of a child whose muscles already were bulging as a newborn apparently because of a dysfunctional myostatin gene.

Source: Medical College of Georgia

Anabolic-androgenic steroids (AAS), commonly know as anabolic steroids, are manufactured substances related to male sex hormones (e.g., testosterone). “Anabolic” refers to muscle-building and “androgenic” refers to increased male sexual characteristics. “Steroids” refers to the class of drugs. These drugs can be legally prescribed to treat conditions resulting from steroid hormone deficiency, such as delayed puberty, but also body wasting in patients with AIDS and other diseases that result in loss of lean muscle mass.

How are AAS Abused?

Some people, both athletes and non-athletes, abuse AAS in an attempt to enhance performance and/or improve physical appearance. AAS are taken orally or injected, typically in cycles of weeks or months interrupted by shorter resting periods (this is referred to as “cycling”). In addition, users often combine several different types of steroids, a practice referred to as “stacking.”

How Do AAS Affect the Brain?

The immediate effects of AAS in the brain are mediated by their binding to androgen and estrogen receptors, which can then shuttle into the cell nucleus to influence patterns of gene expression. Because of this, the acute effects of AAS in the brain are substantially different from those of other drugs of abuse. The most important difference is that AAS are not euphorigenic, meaning that they do not trigger rapid increases in the neurotransmitter dopamine, which are responsible for the “high” that often drives substance abuse behaviors. However, long-term use of AAS can eventually have an impact on some of the same brain pathways and chemicals—such as dopamine, serotonin, and opioid systems—that are affected by drugs of abuse. Considering the combined effect of their complex direct and indirect actions, it is not surprising that AAS can affect mood and behavior in significant ways.

AAS and mental health
Taken together, the preclinical, clinical, and anecdotal reports suggest that steroids may contribute to psychiatric dysfunction. Research shows that abuse of anabolic steroids may lead to aggression and other adverse effects.¹ For example, many users report feeling good about themselves while on anabolic steroids, but extreme mood swings can also occur, including manic-like symptoms that could lead to violence.² Researchers have also observed that users may suffer from paranoid jealousy, extreme irritability, delusions, and impaired judgment stemming from feelings of invincibility.

Addictive potential
Animal studies have shown that AAS are reinforcing; that is, animals will self-administer AAS when given the opportunity, just as they do with other addictive drugs.³ This property is more difficult to demonstrate in humans, but the potential for AAS abusers to become addicted is consistent with their continued abuse despite physical problems and negative effects on social relations.⁴ Also, steroid abusers typically spend large amounts of time and money obtaining the drugs, which is another indication of addiction. Individuals who abuse steroids can experience withdrawal symptoms when they stop taking AAS, such as mood swings, fatigue, restlessness, loss of appetite, insomnia, reduced sex drive, and steroid cravings, all of which may contribute to the need for continued abuse. One of the most dangerous withdrawal symptoms is depression, because, when persistent, it can sometimes lead to suicide attempts.

Research also indicates that some users might turn to other drugs to alleviate some of the negative effects of AAS. For example, a study of 227 men admitted in 1999 to a private treatment center for dependence on heroin or other opioids found that 9.3 percent had abused AAS before trying any other illicit drug. Of these, 86 percent first used opioids to counteract insomnia and irritability resulting from the steroids.⁵

What Other Adverse Effects do AAS Have on Health?

Steroid abuse can lead to serious, even irreversible health problems. Some of the most dangerous among them include liver damage, jaundice (yellowish pigmentation of skin, tissues, and body fluids), fluid retention, high blood pressure, increases in LDL (bad cholesterol), and decreases in HDL (good cholesterol). Other reported effects include renal failure, severe acne, and trembling. In addition, there are some gender- and age-specific adverse effects:

• For men—shrinking of the testicles, reduced sperm count, infertility, baldness, development of breasts, increased risk for prostate cancer
• For women—growth of facial hair, male-pattern baldness, changes in or cessation of the menstrual cycle, enlargement of the clitoris, deepened voice
• For adolescents—stunted growth due to premature skeletal maturation and accelerated puberty changes; adolescents risk not reaching their expected height if they take AAS before the typical adolescent growth spurt

In addition, people who inject AAS run the added risk of contracting or transmitting HIV/AIDS or hepatitis, which causes serious damage to the liver.

What Treatment Options Exist?

There has been very little research on treatment for AAS abuse. Current knowledge derives largely from the experiences of a small number of physicians who have worked with patients undergoing steroid withdrawal. They have learned that, in general, supportive therapy combined with education about possible withdrawal symptoms is sufficient in some cases. Sometimes, medications can be used to restore the balance of the hormonal system after its disruption by steroid abuse. If symptoms are severe or prolonged, symptomatic medications or hospitalization may be needed.

How Widespread is AAS Abuse?

Monitoring the Future*
Monitoring the Future is an annual survey used to assesses drug use among the Nation’s 8th-, 10th-, and 12th-grade students. Steroid use among all three grades remained unchanged from 2006 to 2007, for both boys and girls, although significant reductions were noted since 2001 for lifetime and past-year use among all grades, and for past-month use among 8th and 10th graders. Among seniors in 2007, past-year steroid use was reported by 2.3 percent of boys versus 0.6 percent of girls.

—————————-
Article adapted by Sandco.net Weblog from NIDA.
—————————-