Cellular Signal Block Protects Muscle From Wasting And Improves Muscle Regenera

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Blocking A Cellular Signal Protects Muscle From Wasting After Injury

And Improves Muscle Regeneration

http://www.medicalnewstoday.com/medicalnews.php?newsid=55655

Muscle wasting can occur at all ages as the result of genetic

defects, heart failure, spinal injury or cancer. A therapy to cure

the loss of muscle mass and strength, which has a severe impact on

patients' lives, is desperately sought. Blocking a central signal

molecule, researchers from the Mouse Biology Unit of the European

Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, have now

found a way to protect muscle from degenerating after injury and to

improve muscle healing in mice. The study appears in the current

issue of the Journal of Clinical Investigation and suggests two

molecules with the potential to speed up the regeneration of damaged

muscle as promising drug targets for new therapies against muscle

wasting.

We don't realise it when it is working fine, but our muscle is an

intricate system that depends on a well regulated balance of protein

production and breakdown. When this balance gets disturbed by

disease or injury our muscles fade away, and with them our strength.

A crucial player in this process is the signalling molecule NF-kB.

It is well known as a messenger of inflammation and has recently

been implicated in other degenerative conditions such as multiple

sclerosis. The groups of Nadia Rosenthal and Manolis Pasparakis at

the EMBL Mouse Biology Unit have now investigated the role NF-kB

plays in muscle wasting.

First, they genetically removed NF-kB from the leg muscles of mice

by blocking IKK2, a protein needed to activate the signal. Then, to

mimic spinal injury, they blocked the communication between the

spinal cord and the lower leg muscle - an intervention that under

normal circumstances inevitably leads to muscle wasting.

" What we observed was truly amazing " , says Rosenthal, Head of EMBL's

Mouse Biology Unit. " The mice showed hardly any muscle wasting after

the injury; their muscle fibres maintained almost the same size,

strength and distribution as in a healthy muscle. But that's not

all; blocking IKK2 also helped muscle healing. Without the NF-kB

signal the muscle regenerated much better and faster. "

In response to injury or inflammation, NF-kB shuts down the

production of proteins and stimulates their breakdown, which leads

to the loss of muscle substance. Blocking NF-kB has the reverse

effect, protects muscle from wasting and improves healing of already

degenerated muscle.

Protection against muscle atrophy was even stronger when a gene

encoding growth factor IGF-1 was added to muscle tissue lacking NF-

kB. Rosenthal and her lab have been studying IGF-1 for a long time

and have shown in previous studies that the molecule is very good at

promoting repair of skeletal and cardiac muscles.

" The fact that NF-kB reduction helps maintain our muscle mass is a

useful starting point to develop new therapies against muscle

diseases, " says Foteini Mourkioti, who carried out the research in

Rosenthal's lab. " Adding IGF-1 has a similar effect as blocking NF-

kB, but it must act, at least in parts, independently of NF-kB,

because we observed a clear improvement when using the two

treatments together, " she explains.

A combination of IKK2 inhibitors with growth factors like IGF-1,

then seems to be the most promising basis for new therapies against

muscle diseases. The human NF-kB 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.