A Map of Gene Expression Changes with Aging in Human Muscle
Researchers have assembled a map of gene expression changes that occur with aging in human muscle, and here draw some first conclusions from their work:
Aging profoundly affects skeletal muscle, including loss of muscle mass and strength and increasing the levels of fat and connective tissue. This condition, often termed age-related sarcopenia, leads to a variety of physical conditions that reduce life quality and overall health in aging individuals. As we age, we lose approximately 1% of leg lean mass per year and approximately 2.5-4% in leg strength, men to a higher extent than women. This indicates that sarcopenia is not only a matter of loss of muscle mass but rather a concomitant loss of muscle mass and a decline of muscle quality. In order to efficiently delay the onset and severity of sarcopenia, it is crucial to more in detail describe the molecular mechanisms causing this physiological deterioration of muscle function.
Although high-throughput studies of gene expression have generated large amounts of data, most of which is freely available in public archives, the use of this valuable resource is limited by computational complications and non-homogenous annotation. To address these issues, we have performed a complete re-annotation of public microarray data from human skeletal muscle biopsies and constructed a muscle expression compendium consisting of nearly 3000 samples. In our meta-analysis, we find 957 genes significantly associated with aging. The data provides substantially more detail to gene-specific effects of the transcriptome and shows more widespread regulation of gene expression associated with aging than previously reported. We further study the pleiotropic associations of the 957 genes associated with aging and show for example that 20 out of the 21 aging genes are also associated with physical capacity but regulated in the opposite direction with increased physical capacity as compared to increased age. The skeletal muscle expression compendium is publicly available at ArrayExpress with accession number E-MTAB-1788.
Expression of genes in all the major complexes in the electron transport chain (ETC), as well as several genes in the PDH complex decreased with aging. These results together with those of others support the view that elderly subjects have a nearly 50% lower oxidative capacity per volume of muscle than younger subjects. At the cellular level, this decrease has been ascribed to a reduction in mitochondrial content and lower oxidative capacity of the mitochondria, i.e., this decrease of mitochondrial constituents could either reflect defective mitochondria or decreased number of mitochondria or both. Several potential regulators of mitochondrial mass and function were identified among the 957 age-associated genes in the current study. We also find that genes that have a function in glucose uptake and energy sensing are strongly affected by aging. For example, we see reduced expression of the γ1 regulatory unit of AMPK with increased age. AMPK is a major energy sensor in skeletal muscle, controlling crucial steps of both glucose and lipid metabolism through the ability to sense AMP levels.
Strikingly, we find that genes that are associated with both aging and physical capacity are largely counteracting. The presented data thereby support efforts to maintain high physical fitness in an aging population to counteract negative effects on mitochondrial function. In particular, we hypothesize that SOCS2 and FEZ2, which show significant associations with age, body mass index (BMI), and physical capacity and acting in the same direction for BMI and age but in the opposite direction for increasing physical capacity, have key regulatory functions in processes that link these three factors. SOCS2 interacts strongly with the activated IGF1R and may play a regulatory role in IGF1 receptor signaling. Age-associated difference in the mRNA level of SOCS2 has previously been demonstrated in muscle from rat, where it was suggested to reflect resistance to the effect of growth hormone. Also, an acute bout of resistance exercise is capable of upregulating SOCS2 in human skeletal muscle. FEZ2 is to our knowledge a novel age-associated gene, the expression of which was altered in the opposite direction with physical capacity.