MYOSTATIN... a muscle cell growth inhibitor
Muscle wasting and weakness are among the most common inherited and acquired disorders and include the muscular dystrophies, cachexia, and age-related muscle wasting (sarcopenia). These conditions pose a substantial burden to patients and public health. Consequently, there is considerable interest in an inhibitor of muscle growth, myostatin, or growth/differentiation factor 8 (GDF-8). The myostatin gene is expressed almost exclusively in cells of skeletal-muscle lineage throughout embryonic development as well as in adult animals and functions as a negative regulator of muscle growth.
Interference with the myostatin gene in mice doubles skeletal-muscle mass. Conversely, overexpression of the myostatin gene leads to a wasting syndrome characterized by extensive muscle loss. In adult animals, myostatin appears to inhibit the activation of satellite cells, which are stem cells resident in skeletal muscle, responsible for muscle cell growth and new muscle protein production.
1. mdx mice [with mutation in dystrophin gene = genetic model of Duchenne's and Becker's
muscular dystrophy. mdx mice that lacked myostatin were found not only to be stronger
and more muscular than mdx counterparts with normal myostatin.
2. Injection of neutralizing monoclonal antibodies directed against myostatin into either wild-type
or mdx mice increased muscle mass and specific
3. mutations in the myostatin gene have been shown to be responsible for the "double-muscling"
phenotype in Belgian Blue and Piedmontese cattle.
4. case study: human child with myostatin mutation, providing strong evidence that myostatin
does play an important role in regulating muscle mass in humans.
|A healthy woman who was a former professional athlete gave birth to a son after a normal pregnancy. The child's birth weight was in the 75th percentile
and he appeared extraordinarily muscular, with protruding muscles in his thighs (figure 1) and upper arms. With the exception of increased tendon reflexes, the physical examination was normal. Hypoglycemia and increased levels of testosterone and insulin-like growth factor I were excluded. Muscular hypertrophy was verified by ultrasonography when the infant was six days of age (figure 1B). Doppler echocardiography and electrocardiography performed soon after birth and every six months thereafter were consistently normal.
At 4.3 years of age physiologic parameters (body-surface area, pulse rate, left ventricular ejection, and cardiac output) appeared normal. The child's motor and mental development has been normal. Now, at 4.5 years of age (June - 2004), he continues to have increased muscle bulk and strength, and he is able to hold two 3-kg dumbbells in horizontal suspension with his arms extended. Ultrasonography showed that the cross-sectional plane of the patient's quadriceps muscle was above the mean value for an age 10 sex-matched controls. Moreover, the thickness of his subcutaneous fat pad was below the mean value for controls. There was no significant difference in the diameter of the femoral bone between the patient and the controls. There was no indication of fibrosis or deposition of fat tissue. next
The child's phenotype [increased muscling and decreased adiposity] is consistent with loss of function mutations for the myostatin gene. Therefore, Markus Schuelke,et al. NEJM, 350:2682-2688 (2004), sequenced all exons and flanking intron regions of the myostatin gene in the child and his mother. A "G --> A transition at nucleotide g.IVS1+5 was present in both alleles of the patient and one allele of his mother. The mutation was confirmed by restriction analysis and was absent in 200 alleles from control subjects with a similar ethnic background, thus excluding a common polymorphism. Measurement of myostatin levels in the patient's serum by electrophoretic analysis showed absence of the myostatin pepetide in the child compared to wild type organisms (Figure 2).
A loss-of-function mutation in the myostatin gene in this case study child, strongly suggests that the inactivation of myostatin has similar effects in humans, mice, and cattle. So far, no significant health problems have been observed in the child.
Since myostatin is also expressed in the heart, close monitored of the child's cardiac function will be pursued, but no detected any signs of cardiomyopathy or a conduction disturbance have been noted.
HYPOTHESIS: The presence of a human myostatin mutation and the experiments noted above suggest the possibility that muscle bulk and strength could be therapeutically increased by the inactivation of myostatin in patients with muscle-wasting conditions.
WYETH Pharmaceuticals: is developing
myostatin blocking drugs (a protein) that might result in muscle growth in
myotonic diseases. Mice experimentation indicates that MYO-029 reduces obesity,
and tyep 2 diabetes symptoms. In 2002 animal trials on MD mice showed muscle
improvement with myostatin blockers and human trials of MYO-029 are to begin in