Laminin 111 restores muscle regenerative capacity

Laminin 111 restores muscle regenerative capacity in alpha 7 integrin mouse model.

What is alpha 7 integrin muscular dystrophy? Alpha 7 integrin dystrophy (alpha 7 integrin myopathy) is a CMD subtype. It is very rare. Only 3 individuals have been currently found to have a mutation in the alpha 7 integrin gene with CMD. With improved diagnostic access (see research update on Dr. Hegde’s chip technology) it is possible that other individuals with alpha 7 integrin CMD will be found. Alpha 7 integrin is found in the extracellular matrix which is the environment surrounding the muscle cells. It is thought to act as a signaling molecule and interacts with laminin. Laminin deficiency leads to a different CMD subtype: MDC1A or merosin deficient CMD.http://www.medicalnewstoday.com/articles/134279.php

The full article:
Rooney JE, Burkin DJ, et al. Laminin 111 restores regenerative capacity in a mouse model for alpha 7 integrin congenital myopathy. AJIP January 2009 174(1): 1-9.

Why happened in this clinical trial?
Dr. Burkin gave mice with alpha 7 integrin deficiency a muscle toxin. When he compared these mice with normal mice (also called control and wild type mice) after getting the muscle toxin, he noticed that there was decreased activation of satellite cells. Satellite cells are the “stem cell” found naturally in muscle which allows stressed muscle to regenerate itself. A muscle can be stressed because of exercise or disease. He noticed that when the muscle was given laminin 111 prior to getting the muscle toxin, the muscle was able to restore itself in the alpha 7 integrin deficient mice.

What does this mean?
This means that by giving laminin, you can induce muscle regeneration and rescue a CMD (alpha 7 integrin) when it is exposed to a muscle toxin. Laminin is a therapy that could work in both MDC1A (merosin deficient CMD/laminin deficient CMD) as well as in other CMDs by protecting the muscle from stressors and upregulating satellite cell activity. The trick as with all therapies targeted at muscle is that the muscle is one of the largest “organs” in the body. You would have to get the drug into all the muscle. Taking a pill doesn’t guarantee that it will be delivered to muscle. Other means of targeting muscle, such as injections, only target local muscle where the injection site is. Viral gene therapy has the potential to deliver a protein (laminin) to all the muscle if the virus infects muscle however, the significant immune response to the virus must be overcome. In addition, the genetic material for the protein must be small enough to fit into a virus.

What is laminin 111? Laminin 111 is a form of laminin present only in embryonic muscle. One of the unanswered questions from this study is whether laminin 111 reverts laminin interaction and alpha 7 integrin signaling to an earlier developmental stage triggering satellite cell activation and muscle repair. This form of laminin was obtained from a highly purified mouse sarcoma cell line and used because of the low immunologic response. It is unclear if it was the type of laminin that led to successful intervention.

How was muscle cell regeneration demonstrated?
Levels of embryonic myosin heavy chain were assessed (eMyHC). eMyHC is normally elevated after muscle repair. There was a decrease in eMyHC response in alpha 7 integrin mice compared to wild type (control/normal mice) when treated with muscle toxin. This response was boosted when alpha 7 integrin mice were injected with laminin 111 prior to receiving muscle toxin. Laminin 111 also restored myofiber size and myoblast proliferation in alpha 7 integrin deficient mice (Pax 7 and MyoD assays).

To read an medical news abstract:

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  • Congenital Muscular Dystrophy

    A group of diseases causing muscle weakness at birth. Several defined genetic mutations cause muscles to break down faster than they can repair or grow. A child with CMD may have various neurological or physical impairments. Some children never gain the ability to walk, while others lose the ability as they grow older. Learn more...

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