Bruce Spiegelman, PhD
Scientists at Dana-Farber Cancer Institute have shown in a laboratory
study that revving up a crucial set of muscle genes counteracts the
damage caused by a form of muscular dystrophy.
Reporting in the April 1 issue of Genes and Development, the
researchers demonstrated that manipulating a genetic molecular switch
increased the genes' activity in the muscles of mice with Duchenne
muscular dystrophy, slowing the disease-associated muscle wasting. The
authors caution that they have not yet found a way to tweak the switch,
known as PGC-1alpha, in humans.
"I think that if we could elevate the levels of PGC-1alpha in the
muscles of patients with Duchenne muscular dystrophy, it is likely that
we could slow or reduce the course of the disease," said Bruce
Spiegelman, PhD, the Dana-Farber researcher who led the team along with
Christoph Handschin, PhD, formerly of Dana-Farber and now at the
University of Zurich. Other authors are from the University of Iowa
College of Medicine.
Duchenne muscular dystrophy (DMD) is the most common type of muscular
dystrophy in children, occurring once in about every 5,000 live births
of boys, and is ultimately fatal. The average age of death is the
mid-teens, and most patients die by their 30s. In the United States,
about 400 to 600 boys are born each year with DMD or Becker Muscular
Dystrophy, a milder form of the disease. The cause is a mutation, either
inherited or occurring spontaneously, that affects a muscle protein
Spiegelman, whose laboratory discovered PGC-1alpha in 1998, led the
new study which was aimed at determining whether increasing levels of
PGC-1alpha in the muscles of mice could increase the activity of genes
that are known to behave abnormally in muscular dystrophy.
PGC-1alpha is known as a "transcriptional coactivator" that functions
as a switch, or perhaps more accurately, like a light dimmer that
increases or decreases the activity of genes under its control.
Exercising a muscle raises PGC-1alpha levels, causing the formation of
more mitochondria, the chemical power plants that create energy in
PGC-1alpha is also required for the normal operation of genes that
control the development of neuromuscular junctions (NMJ) — sites on
muscle fibers where nerves attach and signal the fibers to contract.
Part of the reason that exercise builds stronger muscles is that it
increases PGC-1alpha activity. Conversely, disease or lack of exercise
reduces PGC-1alpha activity, causing a loss of NMJ function and
weakening, or atrophying, of muscles.
Spiegelman's team had previously bred a strain of mice with
higher-than-normal levels of PGC-1alpha in their muscles. Also available
for the research was a mouse model of Duchenne muscular dystrophy, the
MDX mouse. In the new experiment, the scientists bred male
high-PGC-1alpha mice with female MDX mice (the muscular dystrophy gene
is carried by females in mouse and in humans.) As a result, the
offspring of these matings had muscular dystrophy but also had elevated
PGC-1alpha. Using exercise and chemical tests, the researchers compared
muscle function in the offspring with MDX mice having no additional
Both sets of rodents were run on a treadmill for one hour, then again
24 hours later. Normal mice completed the runs easily on both days,
while untreated MDX rodents were exhausted halfway through each run. The
MDX mice with increased PGC-1alpha activity performed almost as well as
normal mice on the first day; their performances decreased on the
second day, but they still did better than the untreated MDX mice on
The exercise tests and microscopic and chemical examinations of the
muscles showed that boosting PGC-1alpha caused "a clear and substantial
improvement in the structure and function of skeletal muscle in this
disease model," the scientists wrote.
Spiegelman said that his team is collaborating with researchers at
the Broad Institute of Harvard and MIT in searching through libraries of
drugs or drug-like compounds already approved by the Food and Drug
Administration that could increase PGC-1alpha levels. Other searches are
going on in the biotech and pharmaceutical industry, added Spiegelman,
who is also a professor of cell biology at Harvard Medical School.
The research was supported by grants from the National Institutes of
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National