Inflammation and Skeletal Muscle Wasting During Cachexia

Abstract

Cachexia is the involuntary loss of muscle and adipose tissue that strongly affects mortality and treatment efficacy in patients with cancer or chronic inflammatory disease. Currently, no specific treatments or interventions are available for patients developing this disorder. Given the well-documented involvement of pro-inflammatory cytokines in muscle and fat metabolism in physiological responses and in the pathophysiology of chronic inflammatory disease and cancer, considerable interest has revolved around their role in mediating cachexia. This has been supported by association studies that report increased levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in some, but not all, cancers and in chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis (RA). In addition, preclinical studies including animal disease models have provided a substantial body of evidence implicating a causal contribution of systemic inflammation to cachexia. The presence of inflammatory cytokines can affect skeletal muscle through several direct mechanisms, relying on activation of the corresponding receptor expressed by muscle, and resulting in inhibition of muscle protein synthesis (MPS), elevation of catabolic activity through the ubiquitin-proteasomal system (UPS) and autophagy, and impairment of myogenesis. Additionally, systemic inflammatory mediators indirectly contribute to muscle wasting through dysregulation of tissue and organ systems, including GCs via the hypothalamus-pituitary-adrenal (HPA) axis, the digestive system leading to anorexia-cachexia, and alterations in liver and adipocyte behavior, which subsequently impact on muscle. Finally, myokines secreted by skeletal muscle itself in response to inflammation have been implicated as autocrine and endocrine mediators of cachexia, as well as potential modulators of this debilitating condition. While inflammation has been shown to play a pivotal role in cachexia development, further understanding how these cytokines contribute to disease progression is required to reveal biomarkers or diagnostic tools to help identify at risk patients, or enable the design of targeted therapies to prevent or delay the progression of cachexia.

Keywords: COPD; atrophy; cachexia; cancer; cytokines; inflammation; muscle wasting.

FIGURE 1

Signaling pathways activated by inflammatory ligands involved in cachexia-related muscle atrophy. Colors refer to transcription factors (orange), proteolytic signaling (orange), kinases (dark blue), adaptor proteins (light blue), and cell surface receptors (pink). HMGB1, high mobility group box 1; S100B, S100 calcium-binding protein B; RAGE, receptor for advanced glycation endproducts; ActRIIB, activin receptor type IIB; TWEAK, tumor necrosis factor-like weak inducer of apoptosis; Fn14, fibroblast growth factor-inducible 14; TNFα, tumor necrosis factor-α; IL, interleukin; JAK, Janus kinase; STAT, signal transducers and activators of transcription; TRAF, TNF receptor associated factor; FoxO, Forkhead box transcription factors; mTOR, mammalian target of rapamycin; IKK, IκB kinase; NF-κB, nuclear factor-κB; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; MyoD, myoblast determination protein 1; MyoG, myogenin; MRF4, myogenic regulatory factor; AP-1, activator protein 1; MuRF-1, muscle RING-finger protein-1; Bnip3, BCL2 interacting protein 3; Gabarapl1, GABA type A receptor associated protein like 1.

FIGURE 2

Schematic representation of the direct and indirect effects of systemic inflammation resulting in muscle wasting. Inflammatory cytokines such as TNF-α and IL-1β can bind to their receptors on the sarcolemma driving skeletal muscle wasting directly. Alternatively, cytokines may elicit their effects indirectly through several mechanisms, including increased myostatin and glucocorticoid signaling, release of S100B and HMGB1 by inflamed tissue, or reduced amino acid (AA) availability.