Abstract
Musculoskeletal aging is detrimental to multiple bodily functions and starts early, probably in the fourth decade of an individual's life. Sarcopenia is a health problem that is expected to only increase as a greater portion of the population lives longer; prevalence of the related musculoskeletal diseases is similarly expected to increase. Unraveling the biological and biomechanical associations and molecular mechanisms underlying these diseases represents a formidable challenge. There are two major problems making disentangling the biological complexity of musculoskeletal aging difficult: (a) it is a systemic, rather than “compartmental,” problem, which should be approached accordingly, and (b) the aging per se is neither well defined nor reliably measurable. A unique challenge of studying any age-related condition is a need of distinguishing between the “norm” and “pathology,” which are interwoven throughout the aging organism. We argue that detecting genes with pleiotropic functions in musculoskeletal aging is needed to provide insights into the potential biological mechanisms underlying inter-individual differences insusceptibility to the musculoskeletal diseases. However, exploring pleiotropic relationships among the system's components is challenging both methodologically and conceptually. We aimed to focus on genetic aspects of the cross-talk between muscle and its “neighboring” tissues and organs (tendon, bone, and cartilage), and to explore the role of genetics to find the new molecular links between skeletal muscle and other parts of the “musculoskeleton.” Identification of significant genetic variants underlying the musculoskeletal system's aging is now possible more than ever due to the currently available advanced genomic technologies. In summary, a “holistic” genetic approach is needed to study the systems's normal functioning and the disease predisposition in order to improve musculoskeletal health.
Highlights
Musculoskeletal aging is detrimental to multiple bodily functions and starts early, probably in the fourth decade of an individual’s life
A unique challenge of studying any age-related process is a need of distinguishing between the “norm” and “pathology,” which are interwoven in the aging
Association of 29C > T polymorphism in the transforming growth factor-β1 gene with lean body mass in community-dwelling Japanese population single nucleotide polymorphism (SNP) in TGFB1 found to be associated with peak bone mass in young healthy Caucasian females Myostatin-null mice had significantly greater cortical bone mineral content and larger entheses than normal mice messenger RNA (mRNA) levels were reduced in response to heavy-resistance strength training in older adults SNPs were associated with hip peak bone mineral density (BMD) variation in Chinese women
Summary
Reviewed by: Sue Bodine, University of California, USA Stewart I. AGEs are produced by the spontaneous non-enzymatic glycation of proteins (Grillo and Colombatto, 2008) and crosslinking These collagen modifications increase the stiffness of muscle connective tissue, thereby contributing to impaired muscle function in the older person (Mann et al, 2011). Diseases are expected to provide some insight into the genetics of common diseases of the musculoskeletal aging, since they share etiology with the latter [see, for example, LRP5 gene, originally discovered in the rare diseases such as high-bone-mass trait and osteoporosis-pseudoglioma (Boyden et al, 2002; Little et al, 2002) but further being associated with BMD and fracture risk in the general population (Ferrari et al, 2005; Kiel et al, 2007; Estrada et al, 2012)]. Loss-of-function of activin type I receptor (ACVR1) in osteoblasts increases bone mass and activates canonical Wnt signaling through suppression of Wnt inhibitors sclerostin (SOST) and DKK1 (Kamiya et al, 2011)
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