making muscle wasting history

Myostatin inhibition

Aim: To increase muscle mass by reducing the levels of the muscle growth inhibitor myostatin.

Background: There are factors that enhance the formation of muscle and factors that inhibit muscle formation (not all tissues have to be muscle and because muscles use a lot of energy, they should not be bigger than necessary). Myostatin is one of the factors that inhibit muscle growth (it lowers the volume of many muscle related genes). When the gene for the myostatin protein is mutated and no myostatin is made, this leads to increased muscle formation in animals (Belgium blue cattle, Texel sheep, greyhounds, mice) and humans. Thus, if it is possible to prevent myostatin from doing its job, this should enhance muscle formation. This could compensate for the loss of muscle tissue in Duchenne patients and can be achieved by antibodies for myostatin (proteins that can specifically bind to other proteins). These bind to myostatin and prevent it from reaching the gene switches and turning down the volume.

Clinical trials: Myostatin antibodies have been tested in healthy volunteers and were deemed safe. They were consecutively tested in adult patients with muscle diseases. While treatment was safe, it did not result in an increase in muscle mass in the patients. However, patients were only treated for 28 days, which might not have been long enough.

Future: The company Acceleron has identified a new myostatin antibody (ACE-031) that outperforms the old one in Duchenne mouse models. This antibody has been tested in healthy volunteers. This was well tolerated and led to increased muscle mass in a dose dependent manner, with an increase of ~1 kg for the highest dose in a period of 2 weeks. A trial with ACE-031 in Duchenne patients has recently started.

Challenge: Myostatin inhibition will lead to expansion of muscle stem cells (satellite cells, see cell transplantation). Due to the continuous muscle damage in Duchenne patients, the number of these muscle cells is reduced and myostatin inhibition may further deplete the pool of muscle stem cells (i.e. the point where no stem cells are left and muscles can no longer be repaired is reached earlier). However, it has not yet been proven that this is indeed the case.

Follistatin gene delivery

Aim: To increase muscle mass by antagonizing the muscle growth inhibitor myostatin.

Background: Follistatin is a protein that inhibits myostation. As is described above, myostatin is a protein that inhibits muscle growth. Thus, by increasing the levels of follistatin, the inhibitor is inhibited, which will lead to an increase in muscle mass. The follistatin gene has been delivered to mice and monkeys using an AAV viral vector (see gene therapy for more details about the challenges and prospects of gene therapy). The injections resulted in an increase in muscle mass and muscle strength.

Clinical trials: A clinical trial where AAV viral vectors with the follistatin gene will be injected in the quadriceps of Becker patients is planned by Nationwide Children’s Hospital (Columbus Ohio). The aim is to assess whether this is safe and whether it can improve quadriceps muscle mass and strength.

(There is a virus that is relatively good at infecting muscle cells, the so called AAV virus. This virus can infect human cells but does is not pathogenic (it does not cause a disease). ) Please see gene therapy page for more information.