Researchers at the Johns Hopkins School of Medicine say they have added evidence that a muscle protein called CaMKII improves strength, endurance, muscle health and fitness in young animals. But their experiments in mice and fruit flies showed that the CaMKII gene also contributes to an evolutionary trade-off: increased susceptibility to age-associated disease, weakness and mortality.

The study, published May 26 in the journal Nature Communications, shows that future treatments targeting CaMKII could prevent old-age diseases, the researchers say.

Evolutionary conservation of genes that allow young individuals to run faster and respond steadily to the fight-or-flight response makes sense: It helps them catch prey or evade predators, thereby ensuring their reproductive success, the study leaders say. However, some of these genes carry a high price that animals have to pay as they get older. A new study shows that turning on CaMKII through a chemical reaction triggered by the addition of oxygen, known as oxidation, enhances these survival responses in young animals. However, oxidative stress increases with age, leading to excessive activation of CaMKII. Increased CaMKII activity has long been linked to the tissue damage seen in heart failure, atrial fibrillation, cancer, lung and neurodegenerative diseases, says study co-leader Mark Anderson, MD, PhD, professor of medicine and director of medicine at Johns Hopkins University School of Medicine.

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

They found that mice with oxidized CaMKII ran on average 150 meters farther and about 5 meters per minute faster than mice with oxidation-resistant CaMKII.

When the researchers took biopsies of muscle tissue from the mice and looked for other genes previously associated with muscle growth, recovery from exercise, improved blood flow and immune cell activation – factors that increase physical endurance – they found that they were activated only in mice with oxidized CaMKII.

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

These experiments are further evidence that aging diseases are natural compromises built into our genetic makeup, says Qingchuan Wang, PhD, co-director of the study and associate professor of medicine at the Johns Hopkins University School of Medicine. “But they give us some hope that it may be possible to influence this genetic architecture to fight age-related diseases.”

The team from Johns Hopkins Medical Institute also conducted experiments on genetically modified fruit flies to see if oxidizable CaMKII leads to similar effects on the performance and health of invertebrates that do not naturally have the oxidation-sensitive CaMKII protein.

The researchers used a gene-cutting and insertion tool called CRISPR to add an 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 modified to produce oxidizable CaMKII climbed higher and 5 mm per second faster than flies with oxidizable CaMKII. The result suggested that physiological levels of oxidative stress might increase physical performance by oxidizing and activating CaMKII.

When the researchers fed flies an antioxidant diet to offset the effects of oxidative stress on modified CaMKII, flies with and without the genetic modification performed identically in a climbing test.

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

In contrast, genetically modified flies with oxidized CaMKII showed a significant decrease in climbing performance under such oxidative stress: They climbed almost 10 mm per second slower than their counterparts fed a normal diet, suggesting that excessive oxidative stress leads to poorer physical performance through oxidation and CaMKII activation.

The researchers made similar observations in fly hearts. They found that the hearts of flies with oxidized CaMKII contracted more forcefully and relaxed faster than the hearts of flies with oxidation-resistant CaMKII. However, the advantage of the genetically modified flies’ hearts in performance was reversed when the researchers neutralized the oxidants with an antioxidant. The researchers also found that the hearts of genetically modified flies were more vulnerable to the damaging effects of excess oxidants, as they became dysfunctional or stopped beating altogether when treated with paraquat, an oxidant-generating chemical.

The most striking finding, Wang said, was that despite better physical performance and cardiac function, genetically modified flies had faster age-related withering and died at a younger age.

“The main role of evolution is to improve the ability to reproduce, including producing more offspring and the ability to find food. Our results confirm that improving longevity or longevity of a species is not always necessary for this,” explains Gabriel Bever, PhD, assistant professor of functional anatomy and evolution at the Johns Hopkins University School of Medicine and one of the study’s co-authors. “In fact, some of the very adaptations that make a species successful also contribute to aging and age-associated disease.”

Overall, the researchers say, these findings could provide new targets for diseases associated with excess oxidative damage and explain why studies of broad-spectrum antioxidants such as vitamins C and E have produced mixed results in treating cardiovascular disease, Parkinson’s disease and Huntington’s disease.

Scientists say developing treatments that specifically target gene regulators such as CaMKII may yield better results.

“For hundreds of millions of years, these diseases have been programmed into animal genomes to torment us at the end of life,” Bever says. “Obviously, we need a better understanding of their evolutionary roots if we hope to find cures.”

The researchers found further evidence that CaMKII activates genes associated with early immune responses, an early vertebrate adaptation that provides adaptability to help defend against infectious diseases. Researchers have found that as people age, abnormal activation of the immune system contributes to systemic and chronic inflammation and increases the risk of developing all major age-related diseases. “The ability of CaMKII to activate the immune response under oxidative stress may provide clues to its involvement in aging and disease,” Wang said.

Funding for this study was provided by the National Heart, Lung and Blood Institute (R35-HL140034, R01-HL124091), the National Institute of Arthritis and Musculoskeletal Diseases (R37-AR055099, R01-AR059179, R21-AR067872-01), the National Institute of Neurological Disorders and Stroke (R01-NS079584, R21-NS108842) and the Mirowski Award from Johns Hopkins University.

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