Skeletal muscle gene expression after myostatin knockout in mature mice

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Physiol Genomics. 2009 Jun 9.

Skeletal muscle gene expression after myostatin knockout in mature mice.

Welle S, Cardillo A, Zanche M, Tawil R.

University of Rochester Medical Center.

There is much interest in developing anti-myostatin agents to reverse or prevent

muscle atrophy in adults, so it is important to characterize the effects of

reducing myostatin activity after normal muscle development.

For assessment of the effect of loss of myostatin signaling on gene expression

in muscle, RNA from mice with postdevelopmental myostatin knockout was analyzed

with oligonucleotide microarrays.

Myostatin was undetectable in muscle within 2 weeks after Cre recombinase

activation in 4-month-old male mice with floxed myostatin genes. Three months

after myostatin depletion, muscle mass had increased 26% (vs. 2% after induction

of Cre activity in mice with normal myostatin genes), at which time the

expression of several hundred genes differed in knockout and control mice at

nominal P < 0.01.

In contrast to previously-reported effects of constitutive myostatin knockout,

postdevelopmental knockout did not downregulate expression of genes encoding

slow isoforms of contractile proteins or genes encoding proteins involved in

energy metabolism.

Several collagen genes were expressed at 20-50% lower levels in the

myostatin-deficient muscles, which had ~25% less collagen than normal muscles as

reflected by hydroxyproline content. Most of the other genes affected by

myostatin depletion have not been previously linked to myostatin signaling. Gene

set enrichment analysis suggested that Smads are not the only transcription

factors with reduced activity after myostatin depletion.

These data reinforce other evidence that myostatin regulates collagen production

in muscle, and demonstrate that many of the previously-reported effects of

constitutive myostatin deficiency do not occur when myostatin is knocked out in

mature muscles.