Mutations in FHL1 are present in several myopathies, including reducing-body myopathy (RBM), but until now, both the molecular mechanisms causing the disease, and the regular function of FHL1 in healthy tissue, remained unknown.

To address this, Cowling et al. overexpressed FHL1 in both transgenic mice and cultured myoblasts. The mice developed skeletal muscle hypertrophy, and showed increased strength and endurance. Overexpression in myoblasts also increased cell fusion, resulting in hypertrophic myotubes. These phenotypes are similar to those caused by the calcineurin/NFAT pathway and, indeed, inhibiting calcineurin blocked the effects of FHL1 overexpression in vitro. The authors showed that FHL1 binds to and enhances the transcriptional activity of NFATc1 in vitro and in vivo.

So what goes wrong when FHL1 is mutated? In RBM, mutant FHL1 accumulates in cytoplasmic aggregates called reducing bodies, probably as a result of misfolding. When these mutants were expressed in cultured myoblasts, they also aggregated, and did not induce hypertrophy. Cowling and colleagues found that NFATc1 was sequestered to the aggregates, and was therefore unable to activate its target genes.

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Article adapted by Sandco from original press release.
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Contact: Rita Sullivan
Rockefeller University Press

Cowling, B.S., J Cell Biol. 2008 Dec 15;183(6):1033-48

The researchers, based at the School of Graduate Entry Medicine and Health in Derby, want to know what sort of exercise we can take and what food we should eat to slow down the natural loss of skeletal muscle with ageing.

The team from the Department of Clinical Physiology, which has over 20 years experience in carrying out this type of metabolic study, need to recruit 16 healthy male volunteers in two specific age groups to help in it’s research.

Skeletal muscles make up about half of our body weight and are responsible for controlling movement and maintaining posture. However, at around 50 years of age our muscles begin to waste at approximately 0.5 per cent to one per cent a year. It means that an 80 year old may only have 70 per cent of the muscle of a 50 year old.

Since the strength of skeletal muscle is proportional to muscle size, such wasting makes it harder to carry out daily activities requiring strength, such as climbing stairs and leads to a loss of independence and an increased risk of falls and fractures.

In order for skeletal muscles to maintain their size, the large reservoirs of muscle protein require constant replenishment in the way of amino acids from protein contained within the food we eat. In fact, amino acids from our food act not only as the building blocks of muscle proteins but also actually ‘tell’ our muscle cells to build proteins.

Recent research from the clinical physiology team has shown that the cause of muscle wasting with ageing appears to be an attenuation of muscle building in response to protein feeding. In other words, as we age we lose the ability to covert the protein in the food we eat in to muscle tissue. The proposed research will investigate the mechanisms responsible for this deficit.

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Article adapted by MD Sports from original press release.
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Contact: Lindsay Brooke
University of Nottingham

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

“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

Muscle strength increased by an average of 8.5 percent among people taking creatine, compared to those who did not use the supplement, according to a recent review of studies. Creatine users also gained an average of 1.4 pounds more lean body mass than nonusers.

The evidence from the studies “shows that short- and medium-term creatine treatment improves muscle strength in people with muscular dystrophies and is well-tolerated,” said lead reviewer Dr. Rudolf Kley of Ruhr University Bochum in Germany.

The review appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

Creatine (creatine monohydrate) is used by muscle tissue in the production of creatine phosphate, which forms the source of energy working muscles use called adenosine triphosphate (ATP).[1] [2] Low levels of creatine have been associated with rheumatoid arthritis, chronic circulatory and respiratory diseases, as well as several muscle diseases, like Duchenne muscular dystrophy.[3]

People with muscular dystrophies can have lower-than-normal levels of creatine, along with increasing muscle weakness as their disease progresses. Since some studies suggest that creatine improves muscle performance in healthy people, many researchers have reasoned that it might be helpful in treating muscle disease.

The Cochrane researchers reviewed 12 studies that included 266 people with different types of muscular dystrophy. People in the studies who took creatine supplements used them for three weeks to six months.

In muscular dystrophies, the proteins that make up the muscles themselves are either missing or damaged. In a related group of disorders called metabolic myopathies, the chemicals that help muscles operate go awry.

Although creatine seemed to help many patients with muscular dystrophies, those with metabolic myopathies gained no more muscle strength or lean body mass than patients who did not use the supplement.

The reason for the contrasting results — creatine’s “fairly consistent” effects in muscular dystrophy and lack of effectiveness in metabolic diseases — is “not entirely clear,” Kley said, calling for more research on treatment for metabolic disorders.

The review was supported by the Neuromuscular Center Ruhrgebiet/Kliniken Bergmannsheil, at Ruhr-University Bochum and the Hamilton Health Sciences Corporation, in Canada. Kley and colleagues have each participated in trials of creatine treatment for muscle disorders, although none of the studies was sponsored by a maker of creatine.

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Article adapted by Sandco from original press release.
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FOR MORE INFORMATION
Health Behavior News Service: hbns-editor@cfah.org

Kley RA, Vorgerd M, Tarnopolsky MA. Creatine for treating muscle disorders. Cochrane Database of Systematic Reviews 2007, Issue 1.

The Cochrane Collaboration is an international nonprofit, independent organization that produces and disseminates systematic reviews of health care interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. Visit http://www.cochrane.org for more information.

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For orignal formulations and designer bodybuilding and sports dietary supplements visit Sports Peformance

Boosting an exercise-related gene in the brain works as a powerful anti-depressant in mice—a finding that could lead to a new anti-depressant drug target, according to a Yale School of Medicine report in Nature Medicine.

“The VGF exercise-related gene and target for drug development could be even better than chemical antidepressants because it is already present in the brain,” said Ronald Duman, professor of psychiatry and senior author of the study.

Depression affects 16 percent of the population in the United States, at a related cost of $83 billion each year. Currently available anti-depressants help 65 percent of patients and require weeks to months before the patients experience relief.

Duman said it is known that exercise improves brain function and mental health, and provides protective benefits in the event of a brain injury or disease, but how this all happens in the brain is not well understood. He said the fact that existing medications take so long to work indicates that some neuronal adaptation or plasticity is needed.

He and his colleagues designed a custom microarray that was optimized to show small changes in gene expression, particularly in the brain’s hippocampus, a limbic structure highly sensitive to stress hormones, depression, and anti-depressants.

They then compared the brain activity of sedentary mice to those who were given running wheels. The researchers observed that the mice with wheels within one week were running more than six miles each night. Four independent array analyses of the mice turned up 33 hippocampal exercise-regulated genes—27 of which had never been identified before.

The action of one gene in particular—VGF—was greatly enhanced by exercise. Moreover, administering VGF functioned like a powerful anti-depressant, while blocking VGF inhibited the effects of exercise and induced depressive-like behavior in the mice.

“Identification of VGF provides a mechanism by which exercise produces antidepressant effects,” Duman said. “This information further supports the benefits of exercise and provides a novel target for the development of new antidepressants with a completely different mechanism of action than existing medications.”

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Article adapted by MD Sports Weblog from original press release.
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Contact: Jacqueline Weaver
Yale University
Nature Medicine ]]> http://sandco.net/blog/?feed=rss2&p=4 http://sandco.net/blog/?p=5 http://sandco.net/blog/?p=5#comments Tue, 30 Dec 2008 01:15:11 +0000 sandco http://sandco.net/blog/?p=5 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.

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Article adapted by Sandco.net Weblog from NIDA.
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