Abstract
Sarcopenia, a core feature of the physical frailty syndrome, is characterized by multisystem physiological dysregulation. No study has explored qualitatively the hierarchical network of relationships among different dysregulated pathways involved in the pathogenesis of sarcopenia. We used 40 blood biomarkers belonging to community‐dwelling prefrail and frail older persons to derive measures of multiple physiological pathways, and structural equation modeling to generate path network models of the multisystem physiological dysregulations associated with muscle mass and function (MMF). Insulin–leptin signaling and energy regulation, anabolic sex steroid regulation (testosterone, leptin), and tissue oxygenation (hemoglobin, red cell count) appear to be primary mediating factors exerting direct influences on MMF. There was additionally secondary mediatory involvement of myocyte‐ and adipocyte‐derived cytokines, hypothalamic pituitary adrenal (HPA) stress hormones (cortisol, DHEAS), glomerular function, and immune cell regulatory and inflammatory cytokines and glycoproteins. We conclude that within a hierarchical network of multisystem physiological dysregulations in sarcopenia, dysregulated anabolic and catabolic pathways via sex steroids and insulin–leptin dual signaling and tissue hypoxemia are primary physiological dysregulations responsible for sarcopenia and frailty.
Highlights
Studies suggest that multiple cellular, hormonal, metabolic, and molecular mechanisms underlie the development of sarcopenia in animal models, including impaired insulin signaling, imbalanced anabolic and catabolic energy metabolism, upregulation of catabolic cytokine expression, immune dysfunction, systemic inflammation, and increased oxidative stress (A Sayer, Stewart, Patel, & Cooper, 2010)
The exact mechanism is not fully understood, as a key anabolic hormone, insulin stimulates muscle growth via secreting insulin‐like growth factor‐1 (IGF‐1) followed by activation of the phosphoinositide 3‐kinase (PI3K) and Akt signaling pathways via mammalian target of rapamycin that controls protein synthesis and the forkhead box O (FOXO) that controls protein degradation
The first tier of primary relationships with muscle mass and function (MMF), indicated by positive biomarker associations with (a) anabolic sex steroid regulation (β = 0.567, p < 0.001), (b) insulin signaling and energy metabolism (β = 0.315, p < 0.001), and (c) oxygen transport and delivery (β = 0.471, p < 0.001), suggests that these are primary processes involved in muscle growth and function that are dysregulated in sarcopenia
Summary
Studies suggest that multiple cellular, hormonal, metabolic, and molecular mechanisms underlie the development of sarcopenia in animal models, including impaired insulin signaling, imbalanced anabolic and catabolic energy metabolism, upregulation of catabolic cytokine expression, immune dysfunction, systemic inflammation, and increased oxidative stress (A Sayer, Stewart, Patel, & Cooper, 2010). KEYWORDS anemia, blood biomarkers, cortisol, cytokines, DHEAS, glomerular, inflammation, insulin, leptin, muscle mass and function, testosterone
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