Overweight mice fed a high-fat diet and given prednisone once a week had improved exercise endurance, became stronger, increased their lean body mass and lost weight, reports a new Northwestern Medicine study. The mice also had increased muscle metabolism.
Prednisone once a week promoted the absorption of nutrients in the muscles.
The researchers also found that these mice had increased levels of adiponectin, a fat-derived hormone that appears to play an important role in protecting against diabetes and insulin resistance.
The researchers also showed that mice that were already overweight by eating a high-fat diet had benefits after prednisone once a week, experienced increased strength, running capacity and lower blood sugar.
“These studies were done on mice. But if the same routes apply in humans, then prednisone once a week can promote obesity,” says senior author Dr. Elizabeth McNally, director of the Center for Genetic Medicine at Northwestern University Feinberg School of Medicine.
McNally is also a Northwestern Medicine physician and Elizabeth J. Ward is a professor of genetic medicine.
“Daily prednisone is known to promote obesity and even metabolic syndrome – a disorder with elevated blood lipids and blood sugar and weight gain,” McNally said. “So these results, where we intermittently ‘pulsate’ the animals with prednisone once a week, are strikingly different. Obesity is a big problem, and the idea that prednisone once a week can promote the absorption of nutrients in the muscles can be an approach to treating obesity. “
The study will be published on April 1 in Journal of Experimental Medicine.
Most of what we know about steroids like prednisone comes from studies that look at what happens when prednisone, a glucocorticoid steroid, is taken every day.
“We see a very different result when taken once a week,” McNally said. “We need to fine-tune the dosage to find out the right amount to make this work in humans, but knowing that adiponectin can be a marker can provide a clue to determine what the right human dose is.”
McNally described the weekly dose as “a bolus, or nail, of nutrients that enter your muscle.”
“We believe that there is something special about promoting this peak of nutrients in muscles intermittently, and that it can be an effective way to improve lean body mass,” she added.
“What is exciting to me about this work is the discovery that a simple change in the dosing frequency can turn glucocorticoid drugs from inducers to obesity preventers,” says corresponding author Mattia Quattrocelli. “Chronic intake once daily of these drugs is known to promote obesity. Here we show that dosing the same type of drug intermittently – in this case once a week – reverses this effect, promotes muscle metabolism and energy consumption and limits metabolic stress induced of a high-fat diet. “
Quattrocelli, who initiated the research while in the Northwestern, is now an assistant professor at Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics at the University of Cincinnati.
Can weekly doses still be useful for patients with immune systems?
Many patients take prednisone daily for various immune systems. Known side effects of daily prednisone include weight gain and even muscle atrophy with weakness. The investigators want to determine if patients can get the same immune benefit with intermittent prednisone dosing, which can be much more beneficial for the muscle.
Research began in muscular dystrophy
In previously published research, McNally’s team discovered that giving prednisone intermittently was helpful for muscular dystrophy, which showed once a week prednisone improved strength.
The group also recently reported findings from a pilot trial on people with muscular dystrophy where a weekly dose of prednisone improved lean mass.
Not one-size-fits-all for prednisone dosing
People have different reactions to prednisone dosage.
McNally wants to determine which biomarkers are most critical to indicate that they have a beneficial response to prednisone.
“If we can decide how to choose the right dose of prednisone that minimizes atrophy factors and maximizes positive markers like adiponectin, then we can really adjust the dosage of prednisone,” she said.
The group also recently showed that weekly prednisone uses strikingly different molecular pathways to strengthen the muscle in male versus female mice, based on a new study just published in the Journal of Clinical Investigation by Isabella Salamone, a PhD student in McNally’s lab.
The circadian connection
The benefits of weekly prednisone are linked to circadian rhythms, reports another new study from Northwestern and the University of Cincinnati published last month in Science Advances.
Human cortisol and steroid levels increase early in the morning before waking up.
“If you do not give the medicine at the right time of day, you will not get the answer,” Quattrocelli said. “In mice, we had good effects with intermittent prednisone in muscle mass and function when we dose them at the beginning of their daytime. Mice have a circadian rhythm inverted towards us, because they usually sleep during the day and are active at night. This may mean that the optimal the dosing time for humans during the day may be late in the afternoon / early evening, but this must be properly tested. “
Are stronger, slimmer mice equally strong, leaner people?
The big warning is that these studies are being performed on mice, McNally said.
“While we are encouraged by the pilot study on people with muscular dystrophy, mouse muscles have more fast-twitch fibers than humans, and slow muscles may be different,” McNally said. “More studies are needed to try to better understand whether these same mechanisms work in human muscles.”
The study was funded by National Institutes of Health grants DK121875, HL158531, AG049665, AR052646 and HL061322 and the CCHMC Heart Institute Translational Grant.