Muscle atrophy through thick but not thin

June 8, 2009

Ubiquitylating enzyme MuRF1 targets thick fibers in muscle

During desperate times, such as fasting, or muscle wasting that afflicts cancer

or AIDS patients, the body cannibalizes itself, atrophying and breaking down

skeletal muscle proteins to liberate amino acids. In a new study published

online June 8 and in the June 15, 2009 print issue of the Journal of Cell

Biology (www.jcb.org), Shenhav Cohen, Alfred Goldberg, and colleagues show that

muscle atrophy is a more ordered process than was previously thought. These

researchers find evidence that enzyme MuRF1 selectively degrades the thick

filaments in muscle, while bypassing the thin filaments.

We depend on skeletal muscles because they can produce movement, but they serve

another purpose too. " Skeletal muscle is a protein reservoir that can be

mobilized in times of need, " says Goldberg. The structural core of a muscle cell

is the myofibril, composed of myosin-containing thick filaments and

actin-containing thin filaments. During atrophy, this structure is disassembled,

but exactly how was not known. MuRF1, an atrophy-related gene, is a ubiquitin

ligase that " ubiquitylates, " or tags a protein, by attaching a ubiquitin

molecule, marking it for degradation by the cell. It was unclear when and how

ubiquitylation was involved in disassembling skeletal muscles. The researchers

triggered atrophy in mice containing defective MuRF1 (lacking its RING-finger

domain crucial for ubiquitylation). These mutant mice break down less muscle

than wild-type mice, and less ubiquitylation takes place in the mutants.

Cohen and colleagues found that MuRF1 targets the thick filament, demolishing

various components in a specific order. The researchers hypothesize that removal

of certain thick filament components first permits subsequent MuRF1 access to

the myosin heavy chain. However, MuRF1 doesn't exert the same power over the

thin filament, which began to come apart even when MuRF1 was absent.

" Up to now, people thought the muscle just gets smaller " during atrophy,

Goldberg says. Instead, these findings paint a picture of a well-regulated

process of degradation and disassembly. This mechanism " allows the muscle to

still be a muscle and function, " Goldberg says. " Atrophy doesn't just destroy

muscle cells, like apoptosis. " The results indicate that MuRF1 doesn't have to

wait for caspases or calpains to " pre-digest " the myofibril components. The work

also bears on the practical question of whether atrophy can be halted or

reversed with drugs. " It argues against MuRF1 inhibitors " for this purpose,

Goldberg says, because the enzyme is responsible for degrading only some muscle

components, whereas others fall victim to other ubiquitin ligases and autophagy.

Inhibitors that work upstream to block signals that activate ubiquitin ligases

and initiate autophagy are a better bet.

Recommended Posts