Molecular genetic studies of gene identification for sarcopenia.
ABSTRACT Sarcopenia, which is characterized by a progressive decrease of skeletal muscle mass and function with aging, is closely related to several common diseases (such as cardiovascular and airway diseases) and functional impairment/disability. Strong genetic determination has been reported for muscle mass and muscle strength, two most commonly recognized and studied risk phenotypes for sarcopenia, with heritability ranging from 30 to 85% for muscle strength and 45-90% for muscle mass. Sarcopenia has been the subject of increasing genetic research over the past decade. This review is designed to comprehensively summarize the most important and representative molecular genetic studies designed to identify genetic factors associated with sarcopenia. We have methodically reviewed whole-genome linkage studies in humans, quantitative trait loci mapping in animal models, candidate gene association studies, newly reported genome-wide association studies, DNA microarrays and microRNA studies of sarcopenia or related skeletal muscle phenotypes. The major results of each study are tabulated for easy comparison and reference. The findings of representative studies are discussed with respect to their influence on our present understanding of the genetics of sarcopenia. This is a comprehensive review of molecular genetic studies of gene identification for sarcopenia, and an overarching theme for this review is that the currently accumulating results are tentative and occasionally inconsistent and should be interpreted with caution pending further investigation. Consequently, this overview should enhance recognition of the need to validate/replicate the genetic variants underlying sarcopenia in large human cohorts and animal. We believe that further progress in understanding the genetic etiology of sarcopenia will provide valuable insights into important fundamental biological mechanisms underlying muscle physiology that will ultimately lead to improved ability to recognize individuals at risk for developing sarcopenia and our ability to treat this debilitating condition.
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ABSTRACT: Aging is associated with a progressive loss of skeletal muscular function that often leads to progressive disability and loss of independence. Although muscle aging is well documented, the molecular mechanisms of this condition still remain unclear. To gain greater insight into the changes associated with aging of skeletal muscle, we performed quantitative proteomic analyses on young (6-month) and aged (27-month) mouse gastrocnemius muscles using mTRAQ stable isotope mass tags. We identified and quantified a total of 4,585 peptides corresponding to 236 proteins (protein probability > 0.9). Among them, 33 proteins were more than 1.5-fold up-regulated and 20 proteins were more than 1.5-fold down-regulated in aged muscle compared with young muscle. An ontological analysis revealed that differentially expressed proteins belonged to distinct functional groups, including ion homeostasis, energy metabolism, protein turnover, and Ca(2+) signaling. Identified proteins included aralar1, β-enolase, fatty acid-binding protein 3 (Fabp3), 3-hydroxyacyl-CoA dehydrogenase (Hadh), F-box protein 22 (Fbxo22), F-box and leucine-rich repeat protein 18 (Fbxl18), voltage-dependent L-type calcium channel subunit beta-1 (Cacnb1), ryanodine receptor (RyR), and calsequestrin. Ectopic expression of calsequestrin in C2C12 myoblast resulted in decreased activity of nuclear factor of activated T-cells (NFAT) and increased levels of atrogin-1 and MuRF1 E3 ligase, suggesting that these differentially expressed proteins are involved in muscle aging.Proteomics 01/2014; 14(1). DOI:10.1002/pmic.201200497 · 3.97 Impact Factor
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ABSTRACT: It has been approximately 25 years since Dr. Rosenberg first brought attention to sarcopenia. To date, this aging-associated condition is recognized as a chronic loss of muscle mass and is usually accompanied by dynapenia. Despite its poly-etiological factors, sarcopenia has a strong neurogenic component underlying this chrono-degeneration of muscle mass, as shown in recent studies. As it seems plausible to explain the origin of sarcopenia through a motor neuron degeneration model, the focus of sarcopenia research should combine neuroscience with the study of the original myocyte and satellite cells. Although a complete mechanism underlying the development of sarcopenia has yet to be elucidated, we propose that the primary trigger of sarcopenia could be gliogenic in origin based on the close relationship between the glia, neurons and non-neural cells, for example, the motor unit and its associated glia in both the central nervous system (CNS) and the peripheral nervous system (PNS). In addition to muscle cells, both of the neural cells are affected by aging.Mechanisms of ageing and development 07/2013; 134(9). DOI:10.1016/j.mad.2013.06.001 · 3.51 Impact Factor
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ABSTRACT: Changing demographics make it ever more important to understand the modifiable risk factors for disability and loss of independence with advancing age. For more than two decades there has been increasing interest in the role of sarcopenia, the age-related loss of muscle or lean mass, in curtailing active and healthy aging. There is now evidence to suggest that lack of strength, or dynapenia, is a more constant factor in compromised wellbeing in old age and it is apparent that the decline in muscle mass and the decline in strength can take quite different trajectories. This demands recognition of the concept of muscle quality; that is the force generating per capacity per unit cross-sectional area (CSA). An understanding of the impact of aging on skeletal muscle will require attention to both the changes in muscle size and the changes in muscle quality. The aim of this review is to present current knowledge of the decline in human muscle mass and strength with advancing age and the associated risk to health and survival and to review the underlying changes in muscle characteristics and the etiology of sarcopenia. Cross-sectional studies comparing young (18-45 years) and old (>65 years) samples show dramatic variation based on the technique used and population studied. The median of values of rate of loss reported across studies is 0.47% per year in men and 0.37% per year in women. Longitudinal studies show that in people aged 75 years, muscle mass is lost at a rate of 0.64-0.70% per year in women and 0.80-00.98% per year in men. Strength is lost more rapidly. Longitudinal studies show that at age 75 years, strength is lost at a rate of 3-4% per year in men and 2.5-3% per year in women. Studies that assessed changes in mass and strength in the same sample report a loss of strength 2-5 times faster than loss of mass. Loss of strength is a more consistent risk for disability and death than is loss of muscle mass.Frontiers in Physiology 07/2012; 3:260. DOI:10.3389/fphys.2012.00260