BioWorld International Correspondent
LONDON - New and exciting therapies to prevent the muscle wasting that occurs in diseases as diverse as cancer and muscular dystrophy could follow the identification of a molecule that influences muscle degeneration.
The molecule, NF-kappaB, is produced in muscle cells following damage, and is manufactured at higher than normal levels in the muscles of people with Duchenne muscular dystrophy.
A team of European researchers now has shown that inhibiting NF-kappaB in a mouse model of muscle wasting protected the animals' muscles from degeneration. When they combined that strategy with a growth factor also known to protect against muscle atrophy, they obtained even better results.
Nadia Rosenthal, head of the Mouse Biology Unit of the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, told BioWorld International: "What we observed was truly amazing. The mice [in the experiment] showed hardly any muscle wasting after the injury; their muscle fibers maintained almost the same size, strength and distribution as in a healthy muscle."
Rosenthal and her colleagues described their study in a paper in the Nov. 1, 2006, issue of the Journal of Clinical Investigation titled, "Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration."
Muscle wasting can affect humans of all ages. It may develop as the result of genetic defects (such as muscular dystrophy), following spinal injury or in patients with cancer. It also can affect the heart, a condition known as cardiac cachexia.
Rosenthal and her team decided to investigate the inflammatory pathways likely to be involved in triggering the breakdown of muscle protein.
Many different studies suggested that NF-kappaB was a key player, because it is known to influence the growth and differentiation of muscle cells, and to induce muscle atrophy in mice.
Mice lacking a functional copy of the gene encoding NF-kappaB from conception die as embryos, so the researchers used a targeted knockout approach to create mice lacking active NF-kappaB only in skeletal muscle cells.
The scientists did this indirectly, by removing the gene encoding a molecule called IKK2. The usual function of IKK2 is to phosphorylate a protein that normally is bound to NF-kappaB, keeping the latter inactive.
Tests confirmed that the experimental mice had reduced expression of active NF-kappaB in their skeletal muscles.
In mice, cutting the sciatic nerve normally causes muscles in the lower leg to degenerate. In the mice lacking active NF-kappaB in their skeletal muscle cells, however, some types of muscle fibers increased in number, and the size of the fibers remained unchanged. In treadmill tests, too, the mice could run significantly longer distances than control mice (p<0.05).
In a series of experiments, the researchers showed that the leg muscles of control mice were significantly atrophied at seven, 14 and 28 days after cutting the sciatic nerve, whereas the muscles of the mice in the experimental group grew heavier.
Biochemical experiments showed that the denervated muscles of the control mice induced activation of NF-kappaB, while activation of the molecule was impaired in the denervated muscles of the experimental mice.
Additional investigations showed that, in the muscles of the experimental mice, the absence of active NF-kappaB had the effect of stabilizing muscle homeostasis, by both promoting protein synthesis and by attenuating protein degradation.
Rosenthal and her colleagues knew that the growth factor insulin-like growth factor-1 also could protect against muscle atrophy by increasing protein synthesis and decreasing mechanisms that lead to protein breakdown, such as ubiquitination.
The team therefore decided to cross the experimental mice, which lacked active NF-kappaB in their skeletal muscles, with mice that had been genetically manipulated to express additional amounts of IGF-1 in their skeletal muscles. In the experiment, protection against muscle atrophy was even stronger.
Foteini Mourkioti, who carried out the research in Rosenthal's lab, said: "This experiment showed that adding IGF-1 has a similar effect to blocking NF-kappaB, but it must act, at least in parts, independently of NF-kappaB, because we observed a clear improvement when using the two treatments together."
Writing in the Journal of Clinical Investigation, the authors concluded: "The broad benefits of NF-kappaB blockade in augmenting muscle performance raise new and exciting possibilities for therapeutic approaches in the treatment of muscular disorders and for the development of strategies to attenuate human muscle wasting."
Rosenthal added, "The human NF-kappaB and growth factor signaling networks are very similar to those of mice, so compounds interfering with them are likely to show the same positive effects in humans."