Low-Grade Systemic Inflammation Interferes with Anabolic and Catabolic Characteristics of the Aged Human Skeletal Muscle.

Dimitrios Draganidis,Niki Chondrogianni,Athanasios Poulios,Ioannis Papassotiriou,Chariklia K Deli,Athanasios Z Jamurtas,George Mastorakos,Tobias Jung,Konstantinos Papanikolaou,Ioannis G Fatouros,Kalliopi Georgakouli,Leonidas G Karagounis,Tilman Grune,Nikoletta Papaevgeniou,Constantinos Papadopoulos,Athanasios Chatzinikolaou,Alexios Batrakoulis,Alexandros Georgakilas

doi:10.1155/2021/8376915

Abstract

Aging is associated with the development of chronic low-grade systemic inflammation (LGSI) characterized by increased circulating levels of proinflammatory cytokines and acute phase proteins such as C-reactive protein (CRP). Collective evidence suggests that elevated levels of inflammatory mediators such as CRP, interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) are correlated with deteriorated skeletal muscle mass and function, though the molecular footprint of this observation in the aged human skeletal muscle remains obscure. Based on animal models showing impaired protein synthesis and enhanced degradation in response to LGSI, we compared here the response of proteolysis- and protein synthesis-related signaling proteins as well as the satellite cell and amino acid transporter protein content between healthy older adults with increased versus physiological blood hs-CRP levels in the fasted (basal) state and after an anabolic stimulus comprised of acute resistance exercise (RE) and protein feeding. Our main findings indicate that older adults with increased hs-CRP levels demonstrate (i) increased proteasome activity, accompanied by increased protein carbonylation and IKKα/β phosphorylation; (ii) reduced Pax7+ satellite cells; (iii) increased insulin resistance, at the basal state; and (iv) impaired S6 ribosomal protein phosphorylation accompanied by hyperinsulinemia following an acute RE bout combined with protein ingestion. Collectively, these data provide support to the concept that age-related chronic LGSI may upregulate proteasome activity via induction of the NF-κB signaling and protein oxidation and impair the insulin-dependent anabolic potential of human skeletal muscle.

Highlights

Chronic low-grade systemic inflammation (LGSI) develops with increasing age and is characterized by increased levels of circulating proinflammatory cytokines and acute phase proteins [1]
We provide a human clinical trial comparing the function of proteasome, the satellite cell and amino acid transporter protein content, and phosphorylation and protein content of signaling proteins related to protein synthesis and ribosome biogenesis in skeletal muscle, between healthy older men with elevated hs-C-reactive protein (CRP) and their age-matched counterparts with physiological hs-CRP levels
Of the 11 individuals included in ESI, 10 had a hs-CRP value between 1 and 3 mg/L and only one individual had >3 mg/L

Summary

Introduction

Chronic low-grade systemic inflammation (LGSI) develops with increasing age and is characterized by increased levels of circulating proinflammatory cytokines and acute phase proteins [1]. The transcription factor nuclear factor-kappa B (NF-κB) plays a pivotal role in muscle atrophy, as its activation induces profound muscle loss in mice by upregulating the ubiquitin proteasome system- (UPS-) mediated proteolysis [7, 8] This scenario has been verified by studies using myotudes, revealing that proinflammatory cytokines are capable of inducing protein degradation and skeletal muscle loss via a NF-κB–dependent activation of the UPS [7,8,9]

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