The TWEAK-Fn14 pathway: A potent regulator of skeletal muscle biology in health and disease

Abstract

TNF-like weak inducer of apoptosis (TWEAK), a TNF superfamily ligand, and its bona fide receptor, the TNF receptor superfamily member fibroblast growth factor-inducible protein 14 (Fn14), represents a pivotal axis for shaping both physiological and pathological tissue responses to acute or chronic injury and disease. In recent years significant advances have been made in delineating the prominent role of this axis in regulating skeletal muscle mass and metabolism. Also emerging from the broad study of tissue injury in skeletal muscle and other organs is the role of the TWEAK-Fn14 pathway in promoting fibrosis. This review article highlights recent advancements towards understanding how the TWEAK-Fn14 pathway regulates the response to various skeletal muscle insults and more broadly, engages multiple mechanisms to drive tissue fibrosis.

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

“…The inflammatory cytokine TWEAK and its receptor Fn14 negatively regulate skeletal muscle growth and function (104). However, recent in vivo studies using pharmacological and genetic modulation of TWEAK and Fn14 have also demonstrated a role for this pathway in the development of pathological cardiac hypertrophy, fibrosis, LV remodeling and dysfunction, and heart failure (31,51,81,85).…”

Heightened TWEAK-NF-κB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury

“…TWEAK is a member of the TNF superfamily of cytokines and an important stimulus for the activation of NF-B signaling in skeletal muscle (39,40). TWEAK R, the smallest member of the TNF superfamily, has been identified as the unique TWEAK R (28,31,35).…”

“…TWEAK R contains a TRAF binding site (9), which leads to downstream signaling and NF-B transcriptional regulation upon stimulation by TWEAK. TWEAK R is expressed at low levels in healthy tissues, and its expression significantly increases in response to injury, aging, disuse (40), and acute resistance exercise (33). Short-term TWEAK-TWEAK R activation promotes tissue repair and regeneration following an acute injury; however, during chronic injury or disease conditions, sustained TWEAK-TWEAK R activation may drive these responses toward a pathological remodeling in the muscle in which healthy tissue is replaced by fibrotic tissue (15,39,40).…”

“…The TWEAK-TWEAK R system is also an important regulator of fibrosis in skeletal muscle (39,40). The TWEAK-TWEAK R axis promotes fibrogenic activities through its direct action on stromal cell types, thereby causing the accumulation of myofibroblasts.…”

TNF-like weak inducer of apoptosis (TWEAK) : not so weak after all.

“…In similar fashion, as the environmental demands change due to prolonged inactivity or chronic disease states, the skeletal muscle responds by initiating signaling cascades that lead to muscle atrophy or wasting in a context-dependent manner 10 . Skeletal muscle mass is maintained through a delicate balance between the rate of protein synthesis and degradation 2,11 .…”