Age-related muscle loss and progressive dysfunction in mechanosensitive growth factor signaling

Loss of muscle mass and function (sarcopenia) is one of the most marked problems associated with aging because it has major healthcare as well as socioeconomic implications. The growth hormone/IGF-I axis is regarded as an important regulator of muscle mass. However, it is now appreciated that other tissues in addition to the liver express IGF-I. Also, there are local as well as systemic forms of IGF-I that have different functions. We cloned two different IGF-Is that are expressed by skeletal muscle, and both are derived from the IGF-I gene by alternative splicing. One of these is expressed in response to physical activity, which has now been called "mechanogrowth factor" (MGF). The other is similar to the systemic or liver type (IGF-IEa) and is important as the provider of mature IGF-I required for upregulating protein synthesis. MGF differs from systemic IGF-IEa in that it has a different peptide sequence that is responsible for activating muscle satellite (stem) cells. Therefore, it appears these two forms of IGF-I have different actions and that they are important regulators of muscle growth. Growth hormone treatment apparently upregulates the level of IGF-I gene expression, and when it is combined with resistance exercise more is spliced toward MGF. This results in an increase in muscle cross-sectional area in the elderly subjects who otherwise would produce less MGF. The possibility of ameliorating sarcopenia using MGF delivered as a peptide or by gene therapy will be discussed.