making muscle wasting history

Beta-agonists are hormone-like substances that bind to specific receptor proteins on the outside of cell membranes and then start a chain of chemical reactions, a beta-adrenergic signaling pathway or cascade, to deliver a signal to biological targets inside the cell which are important for controlling protein synthesis and protein degradation. Some beta-agonists are approved drugs like bronchodilators to relax the airway muscles of asthma patients, or used as anabolic agents to improve the size and strength of skeletal muscles, sometimes used illegally by athletes (“doping”).

In the laboratory of Prof. Gordon Lynch of the University of Melbourne, the beta-agonist formoterol was tested with excellent results for its ability to reverse muscle wasting in old rats, a finding with clinical potential to treat older people. These positive results suggested that such “anti-aging drugs” could also be used for a potential therapy for Duchenne muscular dystrophy.

In fact, a small clinical trial with Duchenne and Becker dystrophy patients has already been performed. The participants were treated for 28 weeks with albuterol (8 mg/day) another beta-agonist which is approved for asthma. This low dose was chosen after another one-year trial with adult FSH dystrophy patients (another muscle disease) had shown that at doses of 16 and 32 mg/day, albuterol led to some unacceptable heart problems such as palpitations. The reduced dose in the trial with DMD patients did not cause any side effects but produced only a modest increase of muscle strength which was insufficient for an effective therapy against muscle wasting and weakness.

To prepare another clinical trial with a more powerful beta-agonist, Prof. Lynch and his colleagues treated mdx mice with very low (clinically-relevant) doses of formoterol (25 micrograms/kg). This low dose increased the size and strength of fast-twitch and slow-twitch muscles of the mdx mouse and importantly did not make the muscles more easily fatigued. The effects on the size of the heart were also reduced with low-dose treatment.

As Duchenne patients do not need an enlargement of their hearts, the effect of these drugs on the heart muscles must be avoided while maintaining the positive effects on the skeletal muscles. Separating these two effects is still an important scientific challenge and this is a major focus of Prof. Lynch’s research with these compounds. Another side effect, the downregulation of the receptors for the beta agonists in the muscle cell membranes, which reduces their effect on skeletal muscles, must also be avoided before clinical trials for a long-term treatment of Duchenne boys can be started.