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 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.^1,2 Targeted disruption of the myostatin gene in mice doubles skeletal-muscle mass.¹ Conversely, systemic overexpression of the myostatin gene leads to a wasting syndrome characterized by extensive muscle loss.³ In adult animals, myostatin appears to inhibit the activation of satellite cells, which are stem cells resident in skeletal muscle.^4,5

The lack of myostatin promotes growth of skeletal muscle, and blockade of its activity has been proposed as a treatment for various muscle-wasting disorders. Here, we have examined two independent mouse lines that harbor mutations in the myostatin gene, constitutive null ( Mstn ^−/− ) and compact (Berlin High Line, BEH ^c/c ). We report that, despite a larger muscle mass relative to age-matched wild types, there was no increase in maximum tetanic force generation, but that when expressed as a function of muscle size (specific force), muscles of myostatin-deficient mice were weaker than wild-type muscles. In addition, Mstn ^−/− muscle contracted and relaxed faster during a single twitch and had a marked increase in the number of type IIb fibers relative to wild-type controls. This change was also accompanied by a significant increase in type IIB fibers containing tubular aggregates. Moreover, the ratio of mitochondrial DNA to nuclear DNA and mitochondria number were decreased in myostatin-deficient muscle, suggesting a mitochondrial depletion. Overall, our results suggest that lack of myostatin compromises force production in association with loss of oxidative characteristics of skeletal muscle.