Similar but not the same - Why are specific muscles less susceptible to disease than others in muscular dystrophies?

Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are X-linked
diseases, characterized by progressive muscle degeneration and muscle weakness
resulting in functional disabilities. The cause of muscle degeneration is the
absence, in DMD, or dysfunction, in BMD, of the dystrophin protein. Both
diseases currently lack full market approved therapy and treatment mainly
consists of symptomatic care.
Histologically, muscles in DMD and BMD show fibrosis, inflammation and fat
replacement. These processes start in only a few muscles, whereas nearly all
muscles become involved with progression of the disease. Differences in fat
infiltration are also observed within muscles. Given the fact that the mutant
gene is expressed in all muscles, the specific order between and within muscles
is puzzling. Elucidation of this phenomenon could hold the key for the
development of therapies aiming to preserve the muscles as long as possible.
Dystrophin plays an important role in the mechanical functioning of a muscle
and is believed to protect the muscle against damage due to contractions. As
such, one would expect that the extent to which different muscles are
challenged mechanically plays a role and that muscles which are heavily and/or
constantly used are more prone to degeneration. It is difficult to directly
quantify the mechanical use of an individual muscle during a dynamic movement.
A common, but indirect method is the recording of the instantaneous activation
pattern of muscles using surface electromyography (EMG). An alternative method
is to quantify the use of a muscle by assessing the metabolic results of
exercise using magnetic resonance imaging (MRI). MRI is non-invasive and can
give temporal and spatial information on metabolism and perfusion, and on
structure, displacement and size of specific muscles.
Recent technological advances in image acquisition speed and interleaving of
sequences now enable the acquisition of more characteristics in one imaging
session. To enable such acquisitions, we recently purchased an MRI compatible
ergometer, *the Cardiostep* (Ergospect GmbH, Innsbruck, Austria). With this
ergometer, participants can perform an exercise task mimicking climbing stairs.
The CE marking of the ergometer is in progress for cardiac diagnostics under
stress, but not for our intended use. The construction of the ergometer is
compatible with 3 Tesla (T) and 7T systems.

The primary objectives are to:
1) Adapt and optimize sequences and protocols to enable acquisitions during
exercise with MRI and/or surface EMG.
2) Perform a study in healthy volunteers using the sequences and protocols
developed in 1) to correlate MR and/or surface EMG findings with a database of
muscle MD degeneration patterns.

This experimental study will be conducted at the Leiden University Medical
Center (LUMC). The design of the experiments will depend on the objective
studied. For objective 1, protocol optimization, healthy volunteers will
undergo an MRI measurement lasting one hour at maximum. During this scan, the
participant will be asked to perform an exercise task using an MR-compatible
ergometer mimicking stair walking.
For objective 2, the volunteers will undergo two measurements, both lasting no
more than one hour. The first measurement will be an MRI measurement of muscle
use while performing an exercise task in the scanner using the MR-compatible
ergometer. The second measurement is an surface EMG measurement of muscle
activation while performing an exercise task outside of the scanner. To guide
the EMG electrode placement ultrasound will be used. Depending on the intensity
of the exercise, these two experiments can take place on the same day with 2-4
hours rest in-between.

the participant will be asked to perform an exercise task using an
MR-compatible ergometer mimicking stair walking.

This study has no invasive procedures. Subjects with contraindications for MRI
will be excluded. There are no known risks known associated with the use of
MRI, EMG and ultrasound. Participants have no personal benefit from
participating in this study. The data will support approaches aiming to
preserve the muscles as long as possible.