Cellular and genomic measures of stem cell function in age-related human muscle atrophy

Children'S Research Institute, Washington DC

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Abstract

? DESCRIPTION (provided by applicant): Loss of skeletal muscle mass and strength with increasing age is becoming one of the most important medical issues in the USA and Europe. Increasingly, key morbidities of aging, such as Alzheimer's disease, are associated with loss of muscle and loss of exercise activity. The cellular and molecular basis of age-related progressive loss of muscle is disputed. One hypothesis is that the myogenic reserves of stem-like satellite cells become exhausted and unable to maintain muscle in the face of the need to replace muscle damaged by day- to-day activity. A second is that age-related malfunction reflects the progressive accumulation of damage to the mitochondrial and nuclear genomes within the stressful environment of the muscle fibre. These two main hypotheses are not exclusive of one another. We propose to test these ideas in human muscle by grafting fragments of muscle from cadavers of various ages into immunodeficient host mice where we have shown that the satellite stem cells become activated to form small newly regenerated muscles that closely resemble human muscle in man and are the most authentic model available of a regenerated human muscle in vivo. If the satellite cells become functionally exhausted, it will register as a drop in efficiency and/or effectiveness of regeneration with age of the donor cadaver. Because the regenerated muscle is formed anew, the nuclei and mitochondria within it will not have been previously exposed to the oxidative and free-radical damage within muscle fibres and their genomes will act as a pre- damage standard against which to compare the nuclear and mitochondrial genomes present within the cadaver muscle from which the graft was made. If such genomic damage is a significant part of the aging process, we should detect increasing discrepancies between the graft and cadaver genomes with increasing age of the cadaver. Thus, we will have tested the two main candidate hypotheses of age-related loss of function in human muscle. This project represents a synthesis of expertise between two experienced researchers in the same laboratory with backgrounds in different biological disciplines and with a long history of successful collaborative research.