Maintenance of Skeletal Muscle to Counteract Sarcopenia in Patients with Advanced Chronic Kidney Disease and Especially Those Undergoing Hemodialysis

Abstract

Life extension in modern society has introduced new concepts regarding such disorders as frailty and sarcopenia, which has been recognized in various studies. At the same time, cutting-edge technology methods, e.g., renal replacement therapy for conditions such as hemodialysis (HD), have made it possible to protect patients from advanced lethal chronic kidney disease (CKD). Loss of muscle and fat mass, termed protein energy wasting (PEW), has been recognized as prognostic factor and, along with the increasing rate of HD introduction in elderly individuals in Japan, appropriate countermeasures are necessary. Although their origins differ, frailty, sarcopenia, and PEW share common components, among which skeletal muscle plays a central role in their etiologies. The nearest concept may be sarcopenia, for which diagnosis techniques have recently been reported. The focus of this review is on maintenance of skeletal muscle against aging and CKD/HD, based on muscle physiology and pathology. Clinically relevant and topical factors related to muscle wasting including sarcopenia, such as vitamin D, myostatin, insulin (related to diabetes), insulin-like growth factor I, mitochondria, and physical inactivity, are discussed. Findings presented thus far indicate that in addition to modulation of the aforementioned factors, exercise combined with nutritional supplementation may be a useful approach to overcome muscle wasting and sarcopenia in elderly patients undergoing HD treatments.

Keywords: aging; chronic kidney disease; diabetes; hemodialysis; sarcopenia; skeletal muscle.

Figure 1

Conceptual overlapping among frailty, sarcopenia, and PEW. Aging accelerates frailty and sarcopenia. Advanced CKD/HD is profoundly associated with PEW. Elderly HD patients have the highest risk for these pathological conditions. Among these conditions, skeletal muscle derangement is a common component. CKD, chronic kidney disease; HD, hemodialysis; PEW, protein-energy wasting.

Figure 2

Muscle development and regeneration. During the early stage of development, myoblasts fuse to form multinucleated nascent myotubes that show central nucleation. In a later stage, nuclei migrate to the periphery of mature myotubes, resulting in formation of myofibers. Satellite cells are located between the basal lamina and plasma membrane. For muscle regeneration, satellite cells have a key role. Diverse stimuli including injury activate those cells, which is followed by asymmetric division to conserve the satellite cell pool (self-renewal) and generation of committed myogenic precursors (myoblasts) for regeneration via a process equivalent to development.

Figure 3

Various factors affecting skeletal muscle maintenance in aged patients with advanced CKD/HD. In aged patients with advanced CKD/HD, various factors have interaction with and transduce their effects intracellularly, thus affecting skeletal muscle maintenance. Insulin and IGF-I positively regulate skeletal muscle maintenance via binding of their cognate receptors. Subsequent activation of mTORC1 through PI3K/Akt is necessary for protein synthesis. Simultaneously, insulin-stimulated PI3K/Akt increases FOXO phosphorylation and subsequent inhibition of its translocation into the nucleus. On the other hand, myostatin, a negative regulator, binds to ActRIIB. Subsequent phosphorylation of Smad2/3 reduces Akt activation and decreases FOXO phosphorylation. Intranuclear translocated FOXO activates transcription of MuRF1 and Atrogin-1, which accelerates protein degradation via the ubiquitin-proteasome pathway. Defective mitochondrial quality control (derangements in fusion-fission) leads to ROS production and results in muscle protein degradation. Vitamin D is involved in muscle differentiation and proliferation by binding VDR, which is accompanied by interaction with muscle protein metabolism. Among amino acids, leucin activates mTORC1 by binding to Sestrin2, leading to protein synthesis. In addition, satellite cells, which can be modulated by the various aforementioned factors, may contribute to muscle maintenance. CKD, chronic kidney disease; HD, hemodialysis; ActRIIB, activin type II B receptor; IGF-I, insulin-like growth factor I; mTORC1, mammalian target of rapamycin complex 1; PI3K, phosphatidylinositol-3-kinase; FOXO, forkhead box O; MuRF1, muscle ring finger 1; ROS, reactive oxygen species; VDR, vitamin D receptor; DPP4-I; dipeptidyl peptidase 4 inhibitors.