Muscle protein that makes vertebrates fitter linked to limited lifespan

Researchers at Johns Hopkins Medicine say they have added evidence that a protein called CaMKII improves strength, endurance, muscle health and fitness in young animals. Their experiments with mice and fruit flies, however, revealed that the CaMKII gene also contributes to an evolutionary trade-off: increased susceptibility to diseases associated with age, frailty and mortality.

The research, published May 26 in Nature Communication, indicates that future therapies targeting CaMKII could ward off diseases of old age, researchers say.

The evolutionary conservation of genes that allow young people to run faster and respond robustly to fight-or-flight responses makes sense, according to study leaders: it helps them catch prey or escape predators, thus ensuring their reproductive success. However, some of these genes come at a high price that animals have to pay as they get older. The new research shows that activating CaMKII via a chemical reaction caused by the addition of oxygen, known as oxidation, enhances these survival responses for young animals. However, oxidative stress increases with aging, which leads to excessive activation of CaMKII. Elevated CaMKII activity has long been linked to tissue damage seen in heart failure, atrial fibrillation, cancer, pulmonary and neurodegenerative diseases, says study co-lead Mark Anderson MD, Ph.D. , Professor of Medicine and Head of the Department of Medicine at Johns Hopkins University School of Medicine.

In an effort to further explore oxidative stress and its links to aging and fitness, Anderson and his research team genetically engineered mice to make their CaMKII resistant to oxidation. They then used mouse-sized treadmills to compare the athletic performance of mice with and without CaMKII oxidation.

They found that mice with oxidized CaMKII were able to run, on average, about 150 meters further and about 5 meters per minute faster than mice with oxidation resistant CaMKII.

When researchers biopsied muscle tissue from mice and looked for other genes previously linked to muscle growth, recovery after exercise, improved blood flow, and immune cell activation – factors that increase physical endurance – they found them activated only in mice with oxidizable CaMKII.

Further experiments showed that CaMKII activity in mouse muscle tissue increased the expression of cellular pathways related to inflammation, diabetes, cardiac enlargement, seizures and obesity.

These experiences are further evidence that the diseases of aging are natural compromises built into our genetic makeup, says Qinchuan Wang, Ph.D., co-director and assistant professor of medicine at Johns Hopkins University School of Medicine. “But they give us some hope that it is possible to target this genetic architecture to fight age-related diseases.”

The Johns Hopkins medical team also performed experiments on genetically engineered fruit flies to see if an oxidizable CaMKII produced similar performance and health effects in invertebrates, which do not naturally have a sensitive CaMKII protein. to oxidation.

The researchers used a gene cutter and insert tool called CRISPR to add the oxidation site to the CaMKII gene in fruit fly DNA.

In one experiment, the flies were placed in glass tubes and allowed to climb to the top of the tube. The researchers found that flies genetically engineered to have oxidizable CaMKII soared higher and 5 mm per second faster than flies with oxidation-resistant CaMKII. The result suggests that a physiological level of oxidative stress can improve physical performance by oxidizing and activating CaMKII.

When the researchers fed the flies an antioxidant diet to negate the effects of oxidative stress on the modified CaMKII, flies with and without the genetic modification had similar results in the escalation test.

In another experiment, the researchers fed the flies a diet containing the herbicide paraquat, which overloads the flies with excess oxidants that activate CaMKII only in genetically modified flies, but not unmodified flies. They found that the climbing performance of flies with the oxidant resistant CaMKII gene was not affected by the paraquat diet, which was expected since there is no protein to activate.

In contrast, under such oxidative stress, flies genetically modified with oxidizable CaMKII experienced a significant reduction in their climbing performance: they climbed almost 10 mm per second slower than their counterparts fed a normal diet, which which suggests that excessive oxidative stress results in physical decline through oxidation. and activation of CaMKII.

The researchers made similar observations in the hearts of flies. They found that the hearts of flies with oxidizable CaMKII contracted more strongly and relaxed faster than flies with oxidation resistant CaMKII. However, the performance benefit of the hearts of genetically engineered flies was reversed when the researchers neutralized the oxidants with an antioxidant. Researchers have also found that the hearts of genetically engineered flies are more vulnerable to the damaging effects of an excess of oxidant, as they become dysfunctional or stop beating when treated with paraquat, the oxidant-generating chemical. .

The most striking finding, Wang says, was that despite better physical performance and better heart function, genetically engineered flies experienced faster age-related decline and died at a younger age.

“One of the main roles of evolution is to improve the ability to perpetuate the species, including producing more offspring and being able to find food. Our results claim that improving longevity or the lifespan of a species is not always necessary for this to happen, “explains Gabriel Bever, Ph.D., associate professor of functional anatomy and evolution in the University’s medical school. Johns Hopkins and study collaborator. “In fact, some of the very adaptations that make a species successful also contribute to aging and the diseases associated with age.”

Overall, the researchers say these findings may provide new targets for treating diseases linked to an abundance of oxidative damage and may also explain why studies of broad-spectrum antioxidants, such as vitamins C and E, have has shown mixed results in the treatment of heart disease, Parkinson’s disease and Huntington’s disease.

Scientists say that designing treatments specifically targeting gene regulators such as CaMKII may work better.

“For hundreds of millions of years, these diseases have been programmed into animal genomes to torment us at the end of our lives,” says Bever. “It is obvious that we need a more complete understanding of their evolutionary roots if we ever hope to find cures.”

Researchers found additional evidence that CaMKII activates genes associated with early immune responses, an adaptation of early vertebrates that confers fitness by helping prevent infectious disease. Scientists have found that as people age, abnormal activation of the immune system contributes to systemic and chronic inflammation and increases the risk of all major age-related diseases. “The ability of CaMKII to activate the immune response to oxidative stress may hold the key to its involvement in aging and disease,” explains Wang.