video: Dr. Daniel Kelly describes how mice without the protein PGC-1 lose the ability to exercise. view more
Credit: Josh Baxt
ORLANDO, Fla., November 30, 2010 – Daniel Kelly, M.D., and his colleagues at Sanford-Burnham Medical Research Institute (Sanford-Burnham) at Lake Nona have unveiled a surprising new model for studying muscle function: the couch potato mouse. While these mice maintain normal activity and body weight, they do not have the energy to exercise. In the December 1 issue of Cell Metabolism, Dr. Kelly's team reports what happens when muscle tissue lacks PGC-1, a protein coactivator that muscles need to convert fuel into energy.
"Part of our interest in understanding the factors that allow muscles to exercise is the knowledge that whatever this machinery is, it becomes inactive in obesity, aging, diabetes and other chronic conditions that affect mobility," Dr. Kelly explained.
Normally, physical stimulation boosts PGC-1 activity in muscle cells, which switches on genes that increase fuel storage, ultimately leading to "trained" muscle (the physical condition most people hope to attain through exercise). In obese individuals, PGC-1 levels drop, possibly further reducing a person's capacity to exercise – creating a vicious cycle. In this study, mice without muscle PGC-1 looked normal and walked around without difficulty, but could not run on a treadmill.
This is the first time that PGC-1 has been completely removed from muscle tissue, providing researchers with a new model to unravel the protein's role in muscle development, exercise and metabolism. So what happens to mice with muscles short on PGC-1? Their mitochondria – the part of the cell that converts fuel into energy – can't function properly, so cells have to work harder to stay vigorous. This extra effort rapidly depletes carbohydrate fuel stores, leading to premature fatigue. In short, PGC-1 is necessary for exercise, but not normal muscle development and activity.
But these mice held another surprise. PGC-1-deficient couch potato mice were not obese and still respond normally to insulin – meaning they are not at risk for developing diabetes despite their sedentary lifestyles and mitochondrial problems. This was unexpected because many scientists believe that dysfunctional mitochondria trigger a cascade of insulin resistance and diabetes. This study dispels that notion, instead suggesting that perhaps malfunctioning mitochondria are a result of diabetes, rather than a cause.
"Lo and behold, even though these animals couldn't run, they showed no evidence of insulin resistance," Dr. Kelly said. "We are now investigating what happens when we boost PGC-1 activity intermittently, as normally occurs when a person exercises."
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung and Blood Institute (NHLBI), institutes within the National Institutes of Health (NIH), and the American Diabetes Association. For more information about Sanford-Burnham research, visit http://beaker.sanfordburnham.org.
Original paper
Zechner C, Lai L, Fong JL, Geng T, Yan Z, Rumsey JW, Collia D, Chen Z, Wozniak DF, Leone TC, Kelly DP. Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity. Cell Metabolism. December 1, 2010.
About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top independent research institutions nationally for NIH grant funding and among the top organizations worldwide for its research impact. From 1999 – 2009, Sanford-Burnham ranked #1 worldwide among all types of organizations in the fields of biology and biochemistry for the impact of its research publications, defined by citations per publication, according to the Institute for Scientific Information. According to government statistics, Sanford-Burnham ranks #2 nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded.
Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a nonprofit public benefit corporation. For more information, please visit www.sanfordburnham.org.
Journal
Cell Metabolism