This article includes items about: muscular dystrophy, gene therapy, muscle repair, Duchenne muscular dystrophy and spinal-bulbar muscular atrophy.
MDA grantee Pier Lorenzo Puri, at the Dulbecco Telethon Institute in Rome, with colleagues in the United States and Italy, has found that a type of compound known as an HDAC (histone deacetylase) inhibitor increases muscle fiber size and reduces signs of scarring and inflammation in mice with muscular dystrophy.
The researchers, who published their findings in the October issue of Nature Medicine, gave HDAC inhibitors to dystrophin-deficient and alphasarcoglycan-deficient mice, which are mouse models of Duchenne and limb-girdle MD, respectively.
After trying three HDAC inhibitors, they selected one called trichostatin A (TSA) as the best. The investigators think the beneficial effects of TSA are due to its ability to increase production of the follistatin protein, which blocks the growth-limiting muscle protein myostatin.
"These data are so far restricted to mice," Puri says, "and will not necessarily extend to humans. However, we have already planned preclinical studies that will define the suitability of these treatments in humans."
Mice missing the dystrophin protein and showing a disease resembling Duchenne muscular dystrophy (DMD) that received the anti-inflammatory drug etanercept (Enbrel) were significantly protected against exercise-related muscle damage, say researchers at the University of Western Australia in Crawley.
Stuart Hodgetts and colleagues, who published their findings in the October issue of Neuromuscular Disorders, injected etanercept into adult mice exposed to an exercise wheel for 48 hours and compared their muscle samples to those of untreated animals.
Muscle fibers from the upper legs of the treated mice showed much less inflammation and better cell survival than did those of the untreated mice. The investigators cite an earlier study in which the anti-inflammatory drug infliximab (Remicade) had similar benefits in dystrophin-deficient mouse muscles.
The authors say that etanercept and infliximab, both of which are approved in the United States for other conditions and have fewer side effects than the corticosteroids now used in DMD, might be useful "to reduce the severity of the disease in DMD and other dystrophies." They caution that "the merit of using these and other emerging, highly targeted anti-inflammatory drugs ... remains to be demonstrated."
Researchers coordinated by Andrew Lieberman, an MDA grantee at the University of Michigan in Ann Arbor, have developed a new mouse model of spinal-bulbar muscular atrophy (SBMA, or Kennedy's disease) that they say will improve understanding of the human disease.
Their method was distinct from one employed by MDA grantee Albert La Spada at the University of Washington-Seattle and colleagues (see "Research Updates," September-October 2006), although both groups used established technologies.
Publishing their results in the October issue of the Journal of Clinical Investigation, they report that, contrary to previous assumptions, SBMA is not only a disease of the muscle-controlling nerve cells (motor neurons), but it also results from direct damage to muscle fibers
"Understanding the muscle disease that occurs in SBMA patients and in our mice may help us define the processes that lead to this disease and may point toward new therapeutic strategies," Lieberman says.
The researchers bred mice with an expanded section of DNA in the ene for the androgen (male hormone) receptor on the X chromosome, the defect known to cause human SBMA. Like men with SBMA, the mice developed shrunken testicles, decreased fertility and weakness.
Castrating the mice (thereby removing all androgen activity) improved their grip strength, and implanting androgen pellets reversed the improvement. This told the researchers that the weakness depends on androgen levels.
La Spada's experiments showed that SBMA-affected mice that retained some androgen receptor function fared better than those without any, which suggested to him that blocking all androgen activity might not be a good idea. In addition, he noted later, blocking male hormones is a "very unappealing therapeutic intervention," not only for the more obvious reasons but because sudden reduction in androgen levels adversely affects brain function.
La Spada says SBMA results from two problems: expanded DNA in the androgen receptor gene, which is toxic when it interacts with androgens; and a lack of normal androgen receptor function, which would allow androgens to help motor neurons withstand stressful conditions.
His mice, which have expanded androgen receptor DNA inserted on an artificial chromosome, show muscle shrinkage resulting from motor neuron damage and have a slowly progressive disease course, like human SBMA.
Lieberman's mice, which have expanded androgen receptor DNA inserted into one of their own chromosomes, show motor neuron damage, as do SBMA patients, as well as direct muscle damage (until now, not suspected in patients). Yet, unlike people with SBMA, they have a more rapid disease course, die early and show disease in muscles of the urinary tract.
"It's good to have different models, because they can provide you with different windows into what's going on in different aspects of the disease process, and because they will be useful in different ways for testing new treatments," La Spada says.