Genetic Tweaks Create Super-Mice w/ Super-Charged Mitochondria

Swiss scientists have discovered that knocking out the nuclear receptor corepressor 1 (NCoR1) gene in the muscles of mice allow the animals to run farther, and faster. Knocking out the same gene in fat cells eliminated the problem of diabetes in the mice. And those are only two tissues, of the many types of tissues in a mouse's body. I wonder if knocking out the NCoR1 gene in human muscles would create a super athlete?

Knocking out a particular gene in muscle lets mice run twice as far as normal. Knocking out the same gene in fat cells allows the animals to put on weight without developing type-2 diabetes.

The discoveries could lead to new treatments for diabetes or for invigorating muscles in elderly people and in those with wasting diseases, say Johan Auwerx of the Federal Polytechnic School of Lausanne, Switzerland, and colleagues.

...Auwerx and his colleagues used a targeted virus to knock out the gene that makes a protein called nuclear receptor corepressor 1 (NCoR1) in the muscle of mice. Without NCoR1, mitochondria, which power cells, keep working at full speed. "Effectively, the mice go further, faster, on the same amount of gas," says Auwerx.

"The treated mice ran an average of 1600 metres in 2 hours, compared with 800 metres for untreated mice," he says.

...Auwerx warns athletes not to try to grow their muscles and stamina illicitly by somehow targeting the NCoR1 protein, however.

"We only know what happens if it's knocked out either in fat or muscle, and it could have serious side effects on other organs," he says. Also, he points out that without NCoR1, all fetuses perish, so it plays a vital but undiscovered role in fetal development. _NewScientist

Right. As if Auwerx' warnings would have any effect on a determined athlete's plans. And there are likely several other ways for athletes to tweak their muscles' genes, to gain an advantage.

One gene, for example, called MYH16, contributes to the development of large jaw muscles in other apes. In humans, MYH16 has been deactivated. (Puny jaws have marked our lineage for as least 2 million years.) Many people have also lost another muscle-related gene called ACTN3. People with two working versions of this gene are overrepresented among elite sprinters while those with the nonworking version are overrepresented among endurance runners. _Slate

More muscle boosting genes:

CNTF 1357 G → A polymorphism and the muscle strength response to resistance training Jnl Appl Physio 2009

Follistatin Gene Delivery Enhances Muscle Growth and Strength in Nonhuman Primates Sci Transl Med 2009

Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors PNAS 2008

Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging PNAS 2009

Genetically boosted athletes are inevitable, once stealth techniques of controlling gene expression and transfer are developed. But that also means that viable means of strengthening the muscles, bones, and other tissues that normally weaken with ageing, will also be within reach. So it's best not to complain too loudly about the athletes who tweak themselves for advantage, so long as the rest of us can win in the game of life.

Abstract from Cell:

Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of nuclear receptor corepressor 1 (NCoR1) in mice leads to enhanced exercise endurance due to an increase of both muscle mass and of mitochondrial number and activity. The activation of selected transcription factors that control muscle function, such as MEF2, PPARβ/δ, and ERRs, underpins these phenotypic alterations. NCoR1 levels are decreased in conditions that require fat oxidation, resetting transcriptional programs to boost oxidative metabolism. Knockdown of gei-8, the sole C. elegans NCoR homolog, also robustly increased muscle mitochondria and respiration, suggesting conservation of NCoR1 function. Collectively, our data suggest that NCoR1 plays an adaptive role in muscle physiology and that interference with NCoR1 action could be used to improve muscle function. _Cell

Cross-posted from an Al Fin Longevity posting

Return to Mitochondria

Mitochondria are the powerhouses of the cell. If the mitochondria are not healthy, the cell will not be healthy. Drug researchers are beginning to make the connection between drug candidates and mitochondrial health. This dawning awareness should lead to some startling developments in treatments for degenerative diseases such as diabetes--perhaps even for chronic fatigue syndrome. Researchers should also now be able to better avoid new drugs that cause side effects due to induced mitochondrial dysfunction.

Mootha and his team zeroed in on five basic features of mitochondria activity, looking at how a library of 2,500 chemical compounds affected mitochondrial toxic byproducts (like all “chemical factories” mitochondria produce their own toxic waste), energy levels, speed with which substances pass through these organelles, membrane voltage, and expression of key mitochondrial and nuclear genes. (Mitochondria contain their own genome, consisting of approximately 37 genes in humans.)

“It’s just like taking your car in for an engine diagnostic,” explains Mootha. “The mechanic will probe the battery, the exhaust system, the fan belt, etc., and as a result will then produce a read-out for the entire system. That’s analogous to what we’ve done.”

As a result of these investigations, Mootha and his group produced three major findings.

First, the team discovered a pathway by which the mitochondria and the cell’s nuclear genome communicate with each other. They found this by discovering that certain drugs actually broke communication between these two genomes. By reverse engineering the drugs’ toxic effects, they may be able to reconstruct normal function.

Second, the team looked at a class of the cholesterol-lowering drugs called statins. Roughly 100 million Americans take statins, and among that group, about 1 million experience muscle cramping and aches. Previous studies suggested that mitochondria were involved, but clinical evidence remained conflicting. Mootha and his colleagues found that three out of the six statins (Fluvastatin, Lovastatin, and Simvastatin) interfered with mitochondria energy levels, as did the blood-pressure drug Propranolol. When combined, the effect was worse.

“It’s likely that a fair number of patients with heart disease are on one of these three statins as well as Propranolol,” says Mootha, “Our cellular studies predict that these patients might be at a higher risk for developing the muscle cramps. Obviously, this is only a hypothesis, but now this is easily testable.”

The third and arguably most clinically relevant finding builds on a paper Mootha coauthored in 2003, a paper that demonstrated how type 2 diabetes was linked to a decrease in the expression of mitochondrial genes. A subsequent and unrelated paper showed a relationship between type 2 diabetes and an increase in mitochondrial toxic byproducts. Mootha’s group decided to query their toolkit and see if there were any drugs that affected both of these functions, drugs that could boost gene expression while reducing mitochondrial waste.

Indeed, they found six compounds that did just that, five of which were known to perturb the cell’s cytoskeleton, that is, the scaffolding that gives a cell its structure.

“Our data shows that when we disrupt the cytoskeleton of the cell, that sends a message to boost the mitochondria, turning on gene expression and dropping the toxic byproducts,” says Mootha. “The connection between the cytoskeleton and mitochondrial gene expression has never been shown before and could be very important to basic cell biology.”

Of the five drugs that did this, one, called Deoxysappanone, is found in green tea and is known to have anti-diabetic effects. Another, called Mebendazole, is used for treating intestinal worm infections. This connection gives a rationale to case reports in which diabetics treated with Mebendazole have described improvements in their glucose levels while on the drug.

The researchers intend to further investigate some of the basic biological questions that this study has raised, foremost being the relationship between the cytoskeleton and mitochondria. They also plan on using this toolkit to develop strategies for restoring normal mitochondrial function in certain metabolic and neurodegenerative conditions where it has broken down.

Nature Biotechnology, February 24, early online edition___Newswise

The connection between mitochondrial health and many other common degenerative diseases--besides diabetes--is there, waiting to be sorted out. Effective treatment for mitochondrial dysfunction is apt to be most widely applicable to a wide range of diseases which were formerly believed to be unrelated to each other.

Alpha Lipoic Acid--An Old Friend Receives New Attention

Alpha lipoic acid has been shown to be a useful health supplement for over ten years. I have personally followed Lester Packer's research on ALA for a dozen years. Now, scientists at the Linus Pauling Institute are belatedly acknowledging what most of us have known all along--alpha lipoic acid shows a lot of promise.

"The evidence suggests that lipoic acid is actually a low-level stressor that turns on the basic cellular defenses of the body, including some of those that naturally decline with age," said Tory Hagen, an LPI researcher and associate professor of biochemistry and biophysics at OSU. "In particular, it tends to restore levels of glutathione, a protective antioxidant and detoxification compound, to those of a young animal. It also acts as a strong anti-inflammatory agent, which is relevant to many degenerative diseases."

Researchers at LPI are studying vitamins, dietary approaches and micronutrients that may be implicated in the aging or degenerative disease process, and say that lipoic acid appears to be one of those with the most compelling promise. It's normally found at low levels in green leafy vegetables, but can also be taken as a supplement.

...."Our studies have shown that mice supplemented with lipoic acid have a cognitive ability, behavior, and genetic expression of almost 100 detoxification and antioxidant genes that are comparable to that of young animals," Hagen said. "They aren't just living longer, they are living better – and that's the goal we're after."

What the OSU researchers now believe is that the role of lipoic acid is not so much a direct one to benefit cells, but rather an indirect aid that "kick starts" declining function in cells and helps them recover the functions that came more easily and naturally in young animals.

In various effects, lipoic acid appears to help restore a cellular "signaling" process that tends to break down in older blood vessels. It reduces mitochondrial decay in cells, which is closely linked to the symptoms of aging. With age, glutathione levels naturally decline, making older animals more susceptible to both free radicals and other environmental toxins – but lipoic acid can restore glutathione function to near normal. And the expression and function of other genes seems to come back to life.

"We never really expected such a surprising range of benefits from one compound," Hagen said. "This is really unprecedented, and we're pretty excited about it."

Source

They may be slow, but at least they are finally going public on ALA, at Linus Pauling.

The combination of alpha lipoic acid with acetyl L-Carnitine appears to help restore youthful function to aging mitochondria. This may eventually be useful in Alzheimer's Disease and other neurodegenerative conditions.

I was particularly disappointed in the Linus Pauling Institute for some of the statements they issued recently discouraging people from taking OTC flavonoids from plants. Based upon some rather pedestrian research dealing with the detectable anti-oxidant activity of several plant flavonoids, the LPI went fairly overboard in discouraging the public from taking these supplements.

Although the LPI admitted that bioflavonoids appeared to be beneficial in reducing M/M in heart disease and cancer, the overall message appeared to be: "They're not as good antioxidants as they're supposed to be, so don't take them."

One expects journalists and social science professors to exhibit such lack of clear thinking, but not world-class bioscientists.

Metabolic Syndrome: Mitochondria in Diabetes and Heart Disease

In a previous post, I discussed the relationship of mitochondrial dysfunction to neurological disorders such as Alzheimer's, Huntington's, Parkinson's disease, and ALS. In another post, I discussed mitochondrial biomarkers of aging. Now evidence is mounting that mitochondria are involved in metabolic syndrome, including diabetes, obesity, heart disease, and related disorders including hypertension and hyperlipidemia. This syndrome accounts for millions of deaths around the world yearly, and accounts for the ongoing disability of many millions more yearly.

In this JCI research article, scientists from Howard Hughes Medical Institute, and Yale University School of Medicine discovered that there were 38% fewer mitochondria in the muscles of healthy but insulin resistant offspring of diabetic parents. This reduction in muscle mitochondria apparently led to a 60% increase in intramyocellular fat, inside the muscle cells, which likely contributes to insulin resistance, and eventually type 2 diabetes. That is an intriguing finding. Read the entire article online here.

Furthermore, Douglas Wallace at UCI has received a sizable grant to study how genetic changes in mitochondria can lead to metabolic disorders, such as type 2 diabetes. According to this newsreport:

"Our receipt of this prestigious Doris Duke Charitable Foundation award is the direct consequence of UCI's vision of becoming a world leader for the new biomedical discipline of mitochondrial medicine," said Wallace, director of the Center for Molecular and Mitochondrial Medicine and Genetics (MAMMAG) at UC Irvine and National Academy of Sciences member.

Mitochondrial medicine offers innovative new perspectives and approaches for addressing the common age-related diseases associated with the metabolic syndrome as well as with forms of blindness, deafness, movement disorders and dementias -- clinical problems that remain elusive to traditional biomedical concepts and approaches.

With the Doris Duke Clinical Interfaces Award -- which will provide funding for five years -- Wallace will lead a multidisciplinary team of UCI researchers, which include physicians Dr. Ping Wang, Dr. Lee-Ming Chuang and Dr. Jay Gargus; biomedical engineer Bruce Tromberg, director of the Beckman Laser Institute; and atmospheric chemists Donald Blake and F. Sherwood Rowland, who received the Nobel Prize in Chemistry in 1995.

The team will study genetic variation in the DNA of mitochondria and its association with the various symptoms of the metabolic syndrome. Wang, Chuang and Gargus will collect mitochondrial samples from metabolic syndrome patients of Chinese heritage in Taiwan and in Southern California. Wallace's team at MAMMAG then will conduct extensive molecular and biochemical studies of these samples to see if variations in mitochondrial DNA as well as environmental factors affect individual predisposition to the clinical symptoms of metabolic syndrome.

Read more here.

Because of the intimate connection to both aging and many debilitating and fatal diseases, mitochondrial medicine presents a tremendous opportunity. Reversing the age-related changes in mitochondria is one of the seven prime interventions of the SENS rejuvenation approach.

Hat tip to New Hope Cancer Blog.

Mitochondrial Dysfunction and Disease

Mitochondria are the powerhouses of the cell. The better your mitochondria perform, the more energy you will have. All of your cells need well-functioning mitochondria, or they will suffer. Mitochondria were probably bacteria, originally. They contain much of their own DNA, and divide like bacteria, with both copies retaining the genome.

Not surprisingly, mitochondria are sensitive to certain antibiotics, like bacteria. In fact, one approach to cancer chemotherapy is to develop an antibiotic that specifically targets the mitochondria of cancer cells. Causing sufficient damage to mitochondria can induce apoptosis of the cell. A lot of research is currently being conducted to clarify the connection of mitochondria with caspase releae and subsequent apoptosis.

Mitochondrial dysfunction participates in neurodegeneration of Huntington disease (HD), Friedreich ataxia, hereditary spastic paraplegia, and rare familial forms of Parkinson disease (PD), Alzheimer disease (AD), and amyotrophic lateral sclerosis (ALS). Although this is only one of the many molecular pathways to neurodegeneration, it is a potentially important one.

In a previous post, I referred to the speculation that chronic fatigue syndrome was related to mitochondrial dysfunction, which could theoretically be caused by any number of micro-organisms including Epstein Barr Virus (EBV). Chemical insult can also cause mitochondrial dysfunction.

The scope of mitochondrial dysfunction is very broad. Some disorders are inherited and manifest in infancy or childhood, many others are acquired in later life. Several dozen known diseases are related to mitochondrial dysfunction.

The good news is that science is getting a better understanding of how mitochondria resist damage.

The SENS approach to life extension includes the preservation of mitochondrial function as one of its basic tenets.

What if we could all have the mitochondrial function of a Lance Armstrong or a champion Iron Man triathlete? That is the short term goal. Longer term, who knows?