The genetic pleiotropy of musculoskeletal aging

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.

Muscle and Bone Mass Loss in the Elderly Population: Advances in diagnosis and treatment

“…During the later years of an individual’s lifespan, there is an accelerated loss of bone tissue, which is probably related to genetic factors [32, 33]. There are multiple genes involved in the control of musculoskeletal interactions [34, 35, 36, 37], such as the alpha actinin-3 (ACTN3) and the myocyte enhancer factor 2C (MEF2C) gene. Alpha Actinin-3 regulates the muscular power performance and it is associated to decreased bone mass, whereas Myocyte Enhancer Factor 2C is responsible for controlling bone development by means of activating chondrocyte hypertrophy [37].…”

“…There are multiple genes involved in the control of musculoskeletal interactions [34, 35, 36, 37], such as the alpha actinin-3 (ACTN3) and the myocyte enhancer factor 2C (MEF2C) gene. Alpha Actinin-3 regulates the muscular power performance and it is associated to decreased bone mass, whereas Myocyte Enhancer Factor 2C is responsible for controlling bone development by means of activating chondrocyte hypertrophy [37]. With “normal” aging, there is a marked increase in the formation of advanced glycation end-products (AGEs) [37].…”

“…Alpha Actinin-3 regulates the muscular power performance and it is associated to decreased bone mass, whereas Myocyte Enhancer Factor 2C is responsible for controlling bone development by means of activating chondrocyte hypertrophy [37]. With “normal” aging, there is a marked increase in the formation of advanced glycation end-products (AGEs) [37]. In bones, AGEs enhance osteoclast-induced bone resorption, modify bone proteins and disturb bone remodeling [37, 38].…”

“…With “normal” aging, there is a marked increase in the formation of advanced glycation end-products (AGEs) [37]. In bones, AGEs enhance osteoclast-induced bone resorption, modify bone proteins and disturb bone remodeling [37, 38]. In addition to genetics, the whole process of maturation, development, and decline of the musculoskeletal system is significantly affected by environmental influences [39].…”

Vitamin K2 Facilitating Inter-Organ Cross-Talk

“…Genes such as myostatin, α-actinin-3, proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and myocyte enhancer factor 2C (MEF-2C) are included in GWAS (genomewide association study) as believed to be involved in a concurrent loss of muscle and bone tissue [3]. Myostatin, on the other hand, has been shown to be a negative regulator of muscle mass.…”