Muscle wasting and weakness are among the most common inherited and acquired disorders and include the muscular dystrophies, cachexia, and age-related wasting. Since there is no generally accepted treatment to improve muscle bulk and strength, these conditions pose a substantial burden to patients as well as to public health. Consequently, there has been considerable interest in a recently described inhibitor of muscle growth, myostatin, or growth/differentiation factor 8 (GDF-8), which belongs to the transforming growth factor β superfamily of secreted proteins that control the growth and differentiation of tissues throughout the body.
…The function of myostatin appears to be conserved across species, since mutations in the myostatin gene have been shown to be responsible for the “double-muscling” phenotype in cattle.10–13 The phenotypes of mice and cattle lacking myostatin and the high degree of sequence conservation of the predicted myostatin protein in many mammalian species have raised the possibility that myostatin may help regulate muscle growth in humans. We report the identification of a myostatin mutation in a child with muscle hypertrophy, thereby providing strong evidence that myostatin does play an important role in regulating muscle mass in humans.
Case Report
A healthy woman who was a former professional athlete gave birth to a son after a normal pregnancy. The identity of the child’s father was not revealed. The child’s birth weight was in the 75th percentile. Stimulus-induced myoclonus developed several hours after birth, and the infant was admitted to the neonatal ward for assessment. He appeared extraordinarily muscular, with protruding muscles in his thighs (Figure 1A) 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 6 days of age (Figure 1B & Figure 1C). Doppler echocardiography and electrocardiography performed soon after birth and every 6 months thereafter were consistently normal. At 4.3 years of age (body-surface area, 0.78 m2), the child had a pulse rate of 95 beats per minute, a left ventricular ejection fraction of 70%, fractional shortening at the midwall of 56%, and a cardiac output of 2.81 liters per minute, with a left ventricular measurement of 3.42 cm during diastole (50th percentile) and 1.99 cm (25th percentile) during systole and respective septal measurements of 0.59 cm (75th percentile) and 0.81 cm (75th percentile).
The stimulus-induced myoclonus gradually subsided after two months. The child’s motor and mental development has been normal. Now, at 4.5 years of age, 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.
Several family members (Figure 1D) have been reported to be unusually strong. Family member II-3 was a construction worker who was able to unload curbstones by hand. The 24-year-old mother of the child (III-5) appeared muscular, though not to the extent observed in her son; she did not report any health problems. No family members aside from the mother were available to provide samples for genetic analysis.
…These results strongly indicate that our patient has a loss-of-function mutation in the myostatin gene, thus suggesting that the inactivation of myostatin has similar effects in humans, mice, and cattle. So far, we have not observed any health problems in the patient. Since myostatin is also expressed in the heart,23 we have closely monitored our patient’s cardiac function but have not yet detected any signs of cardiomyopathy or a conduction disturbance. However, at 4.5 years of age, our patient is still too young for such abnormalities to be ruled out definitively.