RAGE in the pathophysiology of skeletal muscle

Abstract

Emerging evidence suggests that the signalling of the Receptor for Advanced Glycation End products (RAGE) is critical for skeletal muscle physiology controlling both the activity of muscle precursors during skeletal muscle development and the correct time of muscle regeneration after acute injury. On the other hand, the aberrant re-expression/activity of RAGE in adult skeletal muscle is a hallmark of muscle wasting that occurs in response to ageing, genetic disorders, inflammatory conditions, cancer, and metabolic alterations. In this review, we discuss the mechanisms of action and the ligands of RAGE involved in myoblast differentiation, muscle regeneration, and muscle pathological conditions. We highlight potential therapeutic strategies for targeting RAGE to improve skeletal muscle function.

Keywords: AGEs; HMGB1; RAGE; S100B; muscle wasting; myogenesis.

Figure 1

Schematic representation of fl‐RAGE structure and its of ligands. The dominat negative isoform of RAGE (RAGEΔcyto) lacking of cytoplasmatic tail is reported.

Figure 2

Activation of RAGE signalling. Preassembly of RAGE into dimers and multimers is necessary for RAGE to bind ligands and activate downstream signalling pathways. Upon ligand binding, the RAGE's intracellular domain changes its conformation allowing the interaction with intracellular partners. RAGE signalling involves GTPases and kinases that activate transcription factors. RAGE activation leads to changes in gene expression and altered cellular function including migration, survival, cytokine production, inflammation, proliferation, differentation, and upregulation of RAGE expression itself.

Figure 3

Schematics of S100B/RAGE and HMGB1/RAGE interactions in low‐density (LD) and high‐density (HD) myoblasts. In LD myoblast cultures, interaction of S100B or HMBG1 with RAGE results in the simultaneous stimulation of proliferation and activation of the myogenic programme (left). In HD myoblast cultures, HMGB1‐activated RAGE promotes myoblast differentiation, apoptosis, and myocyte fusion into myofibres (right). HMGB1‐dependent RAGE activation induces p38 MAPK‐dependent expression of myogenin, which upregulates MyoD and represses PAX7 expression, leading to the reduction of proliferation and terminal differentiation. In HD condition, S100B binds bFGF, and the S100B/bFGF complex crosslinks RAGE and FGFR1 on apposed cells, blocking RAGE signalling and enhancing FGFR1 signalling.

Figure 4

Role of RAGE in acute or chronic muscle injury. Upon acute skeletal muscle injury, re‐expressed RAGE in activated satellite cells results in their proliferation and differentiation ultimately leading to regeneration. Under the action of S100B, RAGE signalling promotes proliferation and simultaneously activates the myogenic programme. RAGE activated by HMGB1 causes proliferation arrest and stimulates terminal differentiation of myoblasts into myocytes that build up new myofibres and/or repair damaged myofibres. RAGE‐mediated signalling in infiltrating macrophages modulates the inflammatory response in injured muscles, contributing significantly to accelerate regeneration. S100B/RAGE axis also promotes macrophage infiltration of acutely damaged skeletal muscle and macrophage polarization to M2 phenotype (left). On the contrary, in the course of muscle diseases characterized by chronic inflammation, high glucose conditions, or oxidative stress, an accumulation of RAGE ligands occurs in the serum and damaged myofibres. The overexpressed and overstimulated RAGE amplifies the inflammatory response by stimulating proinflammatory cytokines secretion, induces apoptosis of myocytes, and causes lethal accumulation of oxidative stress contributing to chronic myofibre damage (right).

Figure 5

Schematic representation of the effects of enforced expression of RAGE in TE671 ERMS cells. RAGE engaged by HMGB1 stimulates myogenic differentiation through activation of MKK6/p38 MAPK and myotube hypertrophy through PI3‐K/Akt. HMGB1/RAGE‐dependent activation of p38 MAPK also causes inactivation of ERK1/2 and JNK with consequent inhibition of proliferation and decrease in cell survival. Induction of RAGE in ERMS cells also results in the expression of myogenin and MyoD so as to cause repression of PAX7 expression and PAX7 proteasomal degradation, ultimately leading to reduction of proliferation, enhancement of apoptosis, and myogenic differentiation. Finally, the reduction of Pax7 expression by the RAGE/myogenin axis causes a reduction of cell migration and invasiveness in ERMS.