Organization of the human myostatin gene and expression in healthy men andHIV-infected men with muscle wasting

Myostatin, a member of the transforming growth factor-beta superfamily, is a genetic determinant of skeletal muscle growth. Mice and cattle with inact ivating mutations of myostatin have marked muscle hypertrophy. However, it is not known whether myostatin regulates skeletal muscle growth in adult me n and whether increased myostatin expression contributes to wasting in chro nic illness. We examined the hypothesis that myostatin expression correlate s inversely with fat-free mass in humans and that increased expression of t he myostatin gene is associated with weight loss in men with AIDS wasting s yndrome. We therefore cloned the human myostatin gene and cDNA and examined the gene's expression in the skeletal muscle and serum of healthy and HIV- infected men. The myostatin gene comprises three exons and two introns, map s to chromosomal region 2q33.2, has three putative transcription initiation sites, and is transcribed as a 3.1-kb mRNA species that encodes a 375-aa p recursor protein. Myostatin is expressed uniquely in the human skeletal mus cle as a 26-kDa mature glycoprotein (myostatin-immunoreactive protein) and secreted into the plasma. Myostatin immunoreactivity is detectable in human skeletal muscle in both type 1 and 2 fibers. The serum and intramuscular c oncentrations of myostatin-immunoreactive protein are increased in HIV-infe cted men with weight loss compared,vith healthy men and correlate inversely with fat-free mass index These data support the hypothesis that myostatin is an attenuator of skeletal muscle growth in adult men and contributes to muscle wasting in HIV-infected men.