Genetic Epidemiology

Studies of muscle biology, including mechanisms of development, atrophy, and hypertrophy, from cell and animal models have provided information about a large number of genes that may have an additional role in sarcopenia during aging. One way to study the roles of such genes in sarcopenia is to use genetic epidemiology (Mehrian-Shai and Reichardt, 2004). Genetic epidemiology studies the association of naturally occurring alleles of genes with the extent or rate of sarcopenia in a clinical cohort. Each allele is assessed as a risk factor or protective factor for the development of sarcopenia in the context of other risk factors as part of a multivariate model. A frequently used technique is to identify single-nucleotide polymorphisms (SNPs) in genes of interest, which are naturally occurring variants where a single base-pair is altered. Advances in genotyping techniques have made the use of multiple SNPs per gene and larger population sizes feasible from a technical and financial perspective. The SNPs are treated as alleles for the purpose of analysis. The functional role of important SNPs can later be evaluated in biochemical, cell, or animal models.

Cell Culture Models

Although intact muscles cannot be grown in culture for sufficient time to develop an ex vivo model of sarcopenia, there is a role for cell culture in sarcopenia research (Peterson, 1995). Vertebrate muscles contain satellite cells that are quiescent myoblasts with the ability to proliferate, differentiate, and fuse together to form new muscle fibers. These new muscle fibers are able to replace damaged fibers in muscles. One theory of sarcopenia is that either the depletion or impairment of satellite cells with age produces the loss of muscle fibers once the remaining satellite cells are unable to repair normal muscle damage (Edstrom and Ulfhake, 2005).

Satellite cells can be isolated either from human donors or experimental animals and grown in culture (Peterson, 1995). The ex vivo culture of satellite cells is valuable for four reasons. First, isolated cells can be studied for replicative potential. In both humans and rats, the doubling capacity of satellite cells has been shown to decrease dramatically from youth to middle age with even further declines seen in old age. Second, satellite cell differentiation and fusion can be studied in culture. Cells isolated from older donors show impairments in the ability to differentiate and fuse to form myotubes compared to cells from young donors. Unfortunately, satellite cells in culture complete only the early steps in differentiation and fusion, as indicated by the failure to transition from the expression of fetal and neonatal myosin heavy chain isoforms to the adult isoforms. This suggests that culture alone has a limited role in the study of the differentiation and fusion steps. However, the use of culture along with reimplantation into experimental animals may overcome this limitation, as discussed further, later. Third, cultures of satellite cells can be used to study changes in gene expression with age. Microarray experiments have been performed using satellite cells isolated from animals of increasing age to analyze global changes in gene expression (Beggs et al., 2004). Finally, culture can be used as a means of modifying satellite cells from experimental animals via viral transfection, followed by reimplantation into either wild-type or transgenic animals. These modified satellite cells have been shown to be able to proliferate and differentiate in vivo and form chimeric muscles (Rando and Blau, 1994). The ex vivo modification allows both marking of the cells with a marker like ^-galactosidase along with genetic modification with the over-expression of normal or mutated proteins or the reduction in gene expression via RNA inhibition (RNAi). The value of this procedure is the ability to study the in vivo role of genes identified through experiments such as microarray.

Animal Models

Human studies can provide insights into the clinical consequences and risk factors for sarcopenia and can suggest mechanisms involved in sarcopenia, but they have important limitations. Experimental animals often have significantly shorter life spans than people, so longitudinal studies can be performed over days, weeks, or months instead of the decades involved in human studies. Also, animals can have controlled environments and an essentially identical genetic background between groups. These properties make animal studies faster and more carefully controlled than clinical studies (Cartee, 1995).

Most experimental animals are amenable to types of experiments that are not possible with people. An important insight into the biology of aging and aging associated changes has been provided by dietary restriction. This intervention involves limiting daily caloric intake and results in an up to 50% increase in overall lifespan, along with a slowing of phenotypic signs of aging. Remarkably, dietary restriction has comparable effects on a large number of laboratory animals. Dietary restriction is extremely difficult for people to follow, but is easily instituted in a laboratory setting where access to food can be readily controlled. The genetics of experimental animals can be readily manipulated either via genetic crosses or the construction of transgenic animals. Transgenic animals that either lack specific genes, carry mutated versions of specific genes, or misexpress specific genes can be constructed and used for study. Experimental preclinical medications are easily tested in animals, and animal studies provide a critical precursor to eventual clinical study of successful therapies.

This section will review the use of the two most commonly used animal models: mice and rats. A limitation of these animals is the two- to three-year life span seen under laboratory conditions. Consequently, there is a need for an animal with a shorter life span. As a result the section will end with a discussion of the nematode Caenorhabditis elegans, which has a two- to three-week life span and develops significant sarcopenia during normal aging.

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