Weekly Prednisone Could Reduce Obesity and Help in Muscular Dystrophy
In a study on obese mice fed a high-fat diet, receiving prednisone once weekly improved their exercise endurance and strength, and their reduced weight. The study was published in the Journal of Experimental Medicine. A previous study had found that weekly prednisone was helpful in muscular dystrophy.
“These studies were done in mice. However, if these same pathways hold true in humans, then once-weekly prednisone could benefit obesity,” explained senior author Dr Elizabeth McNally.
“Daily prednisone is known to promote obesity and even metabolic syndrome – a disorder with elevated blood lipids and blood sugar and weight gain,” Dr McNally said. “So, these results, in which we intermittently ‘pulse’ the animals with once-weekly prednisone, are strikingly different. Obesity is a major problem, and the idea that once-weekly prednisone could promote nutrient uptake into muscle might be an approach to treating obesity.”
The once-weekly prednisone, a glucocorticoid steroid, promoted nutrient uptake into the muscles. The researchers also found these mice had increased adiponectin levels, an adipocyte-secreted hormone involved in protecting against diabetes and insulin resistance. Mice that were already obese from eating a high-fat diet were also found to benefit after once-weekly prednisone, experiencing increased strength, running capacity and lower blood glucose.
Most knowledge on steroids like prednisone is derived from studies of daily doses of prednisone
“We see a very different outcome when it is taken once a week,” Dr McNally said. “We need to fine tune dosing to figure out the right amount to make this work in humans, but knowing adiponectin might be one marker could provide a hint at determining what the right human dose is.”
Dr McNally described the weekly dose as “a bolus, or spike, of nutrients going into your muscle.”
“We think there is something special about promoting this spike of nutrients into muscle intermittently, and that it may be an efficient way to improve lean body mass,” she added.
“What is exciting to me about this work is the finding that a simple change in the dosing frequency can transform glucocorticoid drugs from inducers to preventers of obesity,” said corresponding author Mattia Quattrocelli. “Chronic once-daily intake of these drugs is known to promote obesity. Here we show that dosing the same type of drug intermittently – in this case, once weekly – reverses this effect, promotes muscle metabolism and energy expenditure, and curtails the metabolic stress induced by a fat-rich diet.”
Many patients take prednisone daily for different immune conditions, which has side effects including weight gain and even muscle atrophy with weakness. Investigators want to determine whether patients can get the same immune benefit with intermittent prednisone dosing, which could be much more beneficial to the muscle.
Dr McNally’s team previously found that intermittent prednisone administration was helpful for muscular dystrophy, showing once weekly prednisone improved strength, recently reporting that a pilot trial in humans with muscular dystrophy in which one weekly dose of prednisone improved lean mass.
McNally wants to identify biomarkers most critical to measure a beneficial response to prednisone.
“If we can determine how to choose the right dose of prednisone that minimises atrophy factors and maximises positive markers like adiponectin, then we can really personalise the dosing of prednisone,” she said.
The group also recently showed that weekly prednisone uses strikingly different molecular pathways to strengthening the muscle in male versus female mice, based on a new study just published in the Journal of Clinical Investigation by Isabella Salamone, a graduate student in Dr McNally’s lab.
The benefits of weekly prednisone are linked to circadian rhythms, according to another new study published in Science Advances. Human cortisol and steroid levels spike early in the morning before awakening.
“If you don’t give the drug at the right time of day, you don’t get the response,” Quattrocelli said. “In mice, we obtained 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 to us, as they generally sleep during the daytime and are active at night. This could mean that the optimal dosing time for humans during the day could be in the late afternoon/early evening, but this needs to be appropriately tested.”
Conducting these studies in mice is a major limitation, Dr McNally said.
“While we are encouraged by the pilot study in humans with muscular dystrophy, mouse muscles have more fast-twitch fibres than humans, and slow-twitch muscle could be different,” Dr McNally said. “More studies are needed to try to better understand whether these same mechanisms work in human muscles.”
Source: Northwestern University
