A significant component of musculoskeletal frailty in aging animals is diminished contractile capacity. The relatively high level of protein accumulation required for the assembly of the contractile apparatus require specialized systems to selectively stabilize the proteins and mRNA encoding them and a high level of sustained transcriptional activity driven by muscle-specific and ubiquitous nuclear transcription factors. These studie examine three such factors that are present in relatively high levels in both cardiac and skeletal muscle and that are known to drive expression of a number of muscle-specific genes. These are 1) the serum response factor (SRF), 2) the tinman homeobox analog, Csx 3) and the thyroid hormone receptors. The first two factors are involved in the transcription of a number of muscle-specific genes, including sarcomeric actins, the myosin light chains, myoglobin, and the muscle-specific isoforms of creatine kinase. Reagents are being developed to measure their levels of expression in tissues from young and aging animals. The thyroid receptors also act as nuclear factors involved in tissue-specific expression of specific contractile genes in connection with retinoic acid receptors. Their importance to aging lies in the fact that, in terms of gene expression, aging resembles a hypothyroid state. Activation of the genes, such as the b-myosin heavy chain, that are associated with hypothyroidism may have important functional consequences. Since numerous have failed to provide a consensus on whether thyroid hormone levels actually change with age, we have focussed on possible changes in the level of expression or the types o receptors expressed during aging. Our preliminary indication are that ther are no changes in thyroid receptor subtypes with aging that could account for the changes seen in gene expression. Since transcriptional activation by thyroid receptors requires a heterodimer complex with retinoic acid receptors, we are currently examining the changes that occur in retinoic acid receptor gene expression with age. A precise understanding of the molecular mechanisms by which cardiac and skeletal muscle- specific gene expression is initiated and sustained provides the background for understanding age-associated changes in gene transcription that may contribute to musculoskeletal frailty in the aging.
