Mediators and Patterns of Muscle Loss in Chronic Systemic Inflammation

Abstract

Besides its primary function in locomotion, skeletal muscle (SKM), which represents up to half of human's weight, also plays a fundamental homeostatic role. Through the secretion of soluble peptides, or myokines, SKM interacts with major organs involved in metabolic processes. In turn, metabolic cues from these organs are received by muscle cells, which adapt their response accordingly. This is done through an intricate intracellular signaling network characterized by the cross-talking between anabolic and catabolic pathways. A fine regulation of the network is required to protect the organism from an excessive energy expenditure. Systemic inflammation evokes a catabolic reaction in SKM known as sarcopenia. In turn this response comprises several mechanisms, which vary depending on the nature of the insult and its magnitude. In this regard, aging, chronic inflammatory systemic diseases, osteoarthritis and idiopathic inflammatory myopathies can lead to muscle loss. Interestingly, sarcopenia may persist despite remission of chronic inflammation, an issue which warrants further research. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) system stands as a major participant in muscle loss during systemic inflammation, while it is also a well-recognized orchestrator of muscle cell turnover. Herein we summarize current knowledge about models of sarcopenia, their triggers and major mediators and their effect on both protein and cell growth yields. Also, the dual action of the JAK/STAT pathway in muscle mass changes is discussed. We highlight the need to unravel the precise contribution of this system to sarcopenia in order to design targeted therapeutic strategies.

Sarcopenia in aging, obesity, and cancer

“…Age-dependent muscle catabolic processes leading to sarcopenia are associated with multiple systemic etiologic processes including altered energy balance, mitochondrial dysfunction, oxidative stress, and immune cell alterations leading to Senescence Associated Secretory Phenotypes (SASP) ( 7 ), extracellular matrix alterations ( 8 ) and increased fat mass, all contributing to chronic low grade inflammation which can affect all body systems and organs, particularly skeletal muscle. These proinflammatory processes such as SASP, expanded fat mass, altered extracellular matrix all promote inflammatory cytokine secretion stimulating multiple muscle catabolic processes, including upregulation of muscle atrophy f-box protein (MAF-box) and muscle ubiquitin ring finger-1 ligase (MURF-1) resulting in ubiquitination and degradation of muscle protein ( 9 ). Chronic low-grade inflammatory markers increased during normal aging process (inflammaging) include CRP, IL-1β, IL-6 and TNF ( 10 , 11 ).…”

“…Moreover, physical inactivity is linked to loss of lean body mass, and receipt of chemotherapy is related to increases in fat mass ( 18 , 19 ), all of which contribute to shifts in lean body/fat mass ratios. While many of these markers are noted to be upregulated during the normal aging process ( 9 , 15 , 20 , 21 ), their further increase in association with disease may accelerate the aging process leading to functional decline, age-associated comorbidities including sarcopenia and contribute to inter-individual variation in tolerance and response to cancer therapy ( 22 , 23 ).…”

Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs)

“…When respiratory muscles are impacted by COPD, skeletal muscle wasting or cachexia often develops, in which insulin-like growth factor 1 (IGF-1) signaling plays a major role in promoting disease onset and progression, resulting from the activation of the mTOR signaling pathway [191][192][193][194]. The severity of COPD has been linked to significantly low levels of IGF-1 in serum, with cachectic COPD patients showing decreased protein levels of IGF-1 in muscle [195][196][197][198].…”

Molecular mechanisms of myoprotective action of chondroitin sulfate and glucosamine sulfate in sarcopenia

“…П р о в о с п а л и т е л ь н ы е м е х а н и з м ы с а р к о п е н и и Потеря мышечной массы во время атрофии скелетных мышц характеризуется хроническим воспалением, окислительным стрессом, митохондриальной депрессией миоцитов и усилением апоптоза миоцитов. [25,26].…”