'Marathon Mice' Elucidate Little-known Muscle Type

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'Marathon Mice' Elucidate Little-known Muscle Type

http://www.sciencedaily.com/releases/2007/01/070102132525.htm

Researchers report in the January issue of the journal Cell

Metabolism, published by Cell Press, the discovery of a

genetic " switch " that drives the formation of a poorly understood

type of muscle. Moreover, they found, animals whose muscles were

full of the so-called IIX fibers were able to run farther and at

higher work loads than normal mice could.

The findings could ultimately lead to novel drugs designed to change

the composition of muscle, the researchers said. Such treatments

might have the potential to boost physical strength and endurance in

patients with a variety of muscle wasting conditions.

The research team, led by Bruce Spiegelman of Harvard Medical

School, found that increasing activity of the gene known as PGC-1â

in the skeletal muscles of mice caused them to become crowded with

IIX muscle fibers, which are normally much less prevalent.

" One reason why less is known about IIX fibers is that no one muscle

group is packed with them, " Spiegelman said. " For the first time, we

have a mouse model very enriched in IIX fibers. These mice show a

greatly increased capacity to sustain physical activity. "

Skeletal muscle converts chemical energy into motion and force,

ranging from rapid and sudden bursts of intense activity to

continuous low-intensity work, the researchers said. At one

functional extreme, muscles such as the soleus--a broad, flat muscle

found in the calf of the leg--perform slow but steady activities

such as maintaining posture. At the other extreme, muscles such as

the quadriceps typically perform intense and rapid activities.

To fulfill these varied roles, muscles vary in their proportion

of " slow-twitch " muscle fibers (types I and IIA), ideal for slow and

constant roles, and " fast-twitch " fibers (type IIB), better suited

to rapid and sudden activity of shorter duration. The fiber types

are defined by which " myosin heavy chains " (MHCs) they contain and

by their metabolic capacity, a feature largely determined by the

number of energy-producing mitochondria they house. Myosins are

motor proteins that consist of both " heavy " and " light " amino acid

chains.

While most muscles in mammals contain a mixture of slow- and fast-

twitch fiber types, some muscle beds are enriched for one type or

the other, Spiegelman said. However, adult skeletal muscles also

contain fibers with an abundance of a fourth MHC, type IIX, about

which much less is known.

IIX fibers seem to have the oxidative metabolism of slow-twitch

fibers mixed with the biophysical properties of fast-twitch fibers.

Oxidative metabolism is by far the most efficient way of generating

energy, Spiegelman said.

In the current study, the researchers produced mice with higher than

normal levels of the transcriptional coactivator PGC-1â in their

skeletal muscles. Transcriptional coactivators work with other

cellular factors and machinery to control the activity of other

genes. While earlier studies had found that the related coactivator

PGC-1â plays a role in determining muscle type, the role of PGC-1â

wasn't known.

" The muscle from the PGC-1â transgenic mice was strikingly redder in

appearance than wild-type controls, " indicative of their increased

mitochondrial content, the researchers now report. Upon further

examination, the researchers were surprised to find that the fibers

showed a reduction in I, IIA, and IIB MHCs and as much as a 5-fold

increase in IIX MHC.

Nearly 100% of muscle fibers in the transgenic animals contained

abundant MHC IIX mRNA and protein, they found, as compared to only

15%--20% in normal animals. PGC-1â also changed the muscles'

metabolic characteristics by driving the activity of genes that

spark proliferation of mitochondria.

The PGC-1â animals with more IIX muscle fibers showed a greater

capacity for aerobic exercise, they found. Transgenic mice were able

to run, on average, for 32.5 min to exhaustion, compared to 26 min

for their normal littermates, Spiegelman's group reported.

" These data have potential importance for the therapy of a number of

muscular and neuromuscular diseases in humans, " Spiegelman's group

concluded.

" Many conditions accompanied by loss of physical mobility, including

paraplegia, prolonged bed rest, and muscular dystrophies, involve a

loss of oxidative fibers and their replacement with glycolytic

fibers. This, in turn, results in a further loss of resistance to

fatigue, exacerbating the patient's condition in a downward spiral.

The identification of PGC-1â as a potential mediator of the

development of oxidative type IIX fibers suggests new ways to

modulate muscle fiber type in health and disease. "

The researchers include Zoltan Arany, , Wenli Yang,

Yanhong Ma, Sherry Chin, and Bruce M. Spiegelman of Dana-Farber

Cancer Institute and Harvard Medical School in Boston, MA;

Lebrasseur and Carl of Boston University School of Medicine

in Boston, MA

This work was supported by NIH grants HL079172 to Z.A. and DK54477

and DK61562 to B.M.S.

Arany et al.: " The Transcriptional Coactivator PGC-1b Drives the

Formation of Oxidative Type IIX Fibers in Skeletal Muscle. "

Publishing in Cell Metabolism 5, 35--46, January 2007 DOI

10.1016/j.cmet.2006.12.003 http://www.cellmetabolism.org

Note: This story has been adapted from a news release issued by Cell

Press.