Research Profile - The wrong kind of workout
Dr. Geoffrey Maksym
New research shows that muscle cells surrounding the airways can become better at doing just what they shouldn't: cutting off the air supply in people with asthma
It is a basic principle of pumping up: apply stretch and stress to muscle cells, then give them time to relax and rebuild and they will grow stronger and capable of doing more.
But the cellular response that works so well for the skeletal muscle of a weightlifter's biceps may be just the wrong thing for the smooth muscle of an asthmatic's lungs, according to research by Dr. Geoff Maksym at Dalhousie University.
At a Glance
Who – Dr. Geoffrey Maksym, Associate Professor, Dalhousie University's School of Biomedical Engineering
Issue – As we breathe, we constantly stretch our lungs. In healthy individuals, this leads to lasting expansion of constricted airways. In people with asthma, the opposite happens – further constricting the airways and worsening the asthma.
Approach – Dr. Maksym's lab has analyzed the asthmatic response at the cellular level to demonstrate how this stretch and tone response leads to airways becoming more constricted over time.
Impact – This research opens doors for new investigations to mimic or target the continuous reduction of airway contraction in asthma.
Normally, the act of breathing stretches healthy lungs, leading to expansion of the airways. Dr. Maksym's work suggests that in people with asthma the normal stretching of the airways from breathing, combined with tension, or "tone", from exposure to allergens such as dust mites or mould, causes the smooth muscle cells to grow more efficient at constricting.
"What happens – if you're not actively preventing the allergic response by taking your medication – is your muscle grows, becoming stronger, and the cells become faster at contracting," says Dr. Maksym. "And that makes your asthma worse."
A biomedical engineer, Dr. Maksym has demonstrated this problematic propensity using muscle cells from bronchial tissue grown in a lab and repeatedly stretched, just like what happens when we breathe. It is painstakingly detailed work done by PhD student Sarah Connolly – a cell-by-cell analysis of asthma's impact on a lung's airways.
By demonstrating how this stretch and tone response occurs, he has identified pathways for other investigators to seek therapies to stop the response from occurring or reduce its effects.
"It also tells us that the medications we're already using might be making asthma better by a different means than we thought," says Dr. Maksym.
Many people with asthma who take corticosteroids to alleviate allergic inflammation often also take long-acting beta agonists, which cause a long-term relaxation of the smooth muscle thought to aid in preventing constriction, wheezing and shortness of breath.
"Most of us thought that was pretty much the whole story: relaxation of the muscle is a good thing because the muscles are kept from contracting. But it turns out that it also prevents the stress-response and prevents the smooth muscle from getting a workout as you breathe. If you keep the muscle relaxed, you prevent the muscle from building and doing what is called remodeling. Our work has revealed a novel mechanism by which this relaxation may be preventing asthma from becoming worse."
What's next?
The next challenge, Dr. Maksym says, is to use this new information to help identify other possible drug treatments that might mimic relaxation of the smooth muscle and prevent the remodeling response.
"There are many molecular or chemical pathways that may cause tone and stretch to work together to make muscle more efficient at contracting. No one has identified that mechanism yet, but we believe it exists and is one of the reasons why asthma becomes dangerous."
"We grow airway muscle cells and put them on flexible membranes that stretch, mimicking the effect of breathing. So they continually stretch and relax, stretch and relax. If we also change their tone by adding a little tension, such as would occur during an allergic response, after time the muscle becomes stiffer and more efficient at evoking a larger contraction."
-- Dr. Geoffrey Maksym