Loss of Antioxidant Protein Prevents Muscle Regeneration During Aging


Nrf2 is a protein that regulates the response of cells to oxidative damage, This protein normally sits in the cytoplasm of cells where it is routinely degraded by other proteins. However, once cells are exposed to oxidative damage by ultraviolet light, reactive oxygen species, various chemicals, or other conditions that damage cellular structures, the degradation of Nrf2 slows way down and this protein moves into the nucleus where it binds DNA and stimulates the expression of a host of genes that encode proteins with anti-oxidant activity. Thus Nrf2 is one of the primary cellular defenses against the toxic effects of oxidative stress.

Nrf2 pathway

Researchers at the University of Utah School of Medicine have made mice that lack functional Nrf2 and they found that the stem cells of these mice were seriously impaired.

Raj Soorappan and his colleagues have discovered that the muscles of these Nrf2-deficient mice do not regenerate as they get older.

Soorappan explained: “Physical activity is the key to everything.” He continued: “After this study we believe that moderate exercise could be one of the key ways to induce stem cells to regenerate especially during aging.”

Sarcopenia or the age-related loss of muscle mass, begins in most people around the age of 30. To delay this inevitable slide, muscle=producing stem cells help regenerate muscle lost by means of aging and the production of antioxidant molecules help protect stem cells populations so that they can maintain muscle mass.

However, as we age, the production of reactive oxygen species (ROS) overwhelms our endogenous antioxidant systems, and our stem cell populations take a hit. This compromises our ability to regenerate muscle and other tissues as well.

As previously mentioned, Nrf2 regulates the production of these antioxidant molecules. Soorappan used mice that were 23 months old or older (these are rodent senior citizens to be sure). One group of old mice made normal levels of Nrf2, but the other group had no functional Nrf2 protein. Soorappan and his colleagues put these mice through endurance training to determine the effects of ROS on these animals. Interestingly, the Nrf2-deficient mice showed an inability to mobilize their muscle stem cells (satellite cells) to regenerate their muscles. The Nrf2-containing mice, however, were able to properly regenerate their muscles.

“We now know that the antioxidant protein Nrf2 guards the muscle regeneration process in elderly mice and loss of Nrf2, when combined with endurance exercise stress, can cause severe muscle stem cell impairment,” said Mudhusudhanan Narasimhan, the primary author of this research and a research associate with Soorappan.

Soorappan thinks that by understanding the precise role of Nrf2 in muscle regeneration, he an his co-workers will be able to design more informed therapies of muscle loss in aging animals and humans.

Next on Soorappan’s agenda is to examine the effects of exercise on Nrf2 and whether or not an active lifestyle affects the function of Nrf2 and the efficiency of the anti-oxidant pathway it mediates.

The take-home message for now seems to be: “If you don’t use your muscles, you will lose them. At the same time, overdoing endurance training may detract from muscle regeneration,” said Soorappan.

Advertisements

Published by

mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).