Restoring Osteocalcin Levels Reverses Age-Related Decline in Exercise Capacity

Osteocalcin levels decline with age, one of many age-related changes in production of specific proteins. Researchers here demonstrate that introducing additional osteocalcin restores age-related loss of exercise capacity in mice. This is yet another possibility to add to the list of potential gene therapies that might be developed to offset some of the changes that occur with aging, though as for all such alterations, it doesn't address root causes. Though not mapped at the present time, the view of aging as damage accumulation expects there to be a chain of cause and effect leading from increased cell and tissue damage at the root of aging to a series of consequent changes that leads to a reduction in the gene expression of ostoeclastin.

When we exercise, our bones produce a hormone called osteocalcin that increases muscle performance. Osteocalcin naturally declines in humans as we age, beginning in women at age 30 and in men at age 50. During exercise in mice and humans, the levels of osteocalcin in the blood increase depending on how old the organism is. The researchers observed that in 3-month-old adult mice, osteocalcin levels spiked approximately four times the amount that the levels in 12-month-old mice did when the rodents ran for 40 minutes on a treadmill. The 3-month-old mice could run for about 1,200 meters before becoming exhausted, while the 12-month-old mice could only run half of that distance.

To investigate whether osteocalcin levels were affecting exercise performance, researchers tested mice genetically engineered so the hormone couldn't signal properly in their muscles. Without osteocalcin muscle signaling, the mice ran 20%-30% less time and distance than their healthy counterparts before reaching exhaustion. Surprisingly, when healthy mice that were 12 and 15 months old - whose osteocalcin levels had naturally decreased with age - were injected with osteocalcin, their running performance matched that of the healthy 3-month-old mice. The older mice were able to run about 1,200 meters before becoming exhausted. "It was extremely surprising that a single injection of osteocalcin in a 12-month-old mouse could completely restore its muscle function to that of a 3-month-old mouse."

To determine the cellular mechanisms behind osteocalcin's effects, the team measured levels of glycogen, glucose, and acylcarnitines (an indicator of fatty-acid use) in mice with and without osteocalcin. The researchers determined that the hormone helps muscle fibers uptake and catabolize glucose and fatty acids as nutrients during exercise. "It's never been shown before that bone actually influences muscle in any way. Osteocalcin is not the only hormone responsible for adaptation to exercise in mice and humans, but it is the only known bone-derived hormone that increases exercise capacity. This may be one way to treat age-related decline in muscle function in humans."


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