Skeletal muscle redox signaling in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis and the presence of serum autoantibodies. In addition, skeletal muscle weakness is a common comorbidity that contributes to inability to work and reduced quality of life. Loss in muscle mass cannot alone account for the muscle weakness induced by RA, but instead intramuscular dysfunction appears as a critical factor underlying the decreased force generating capacity for patients afflicted by arthritis. Oxidative stress and associated oxidative post-translational modifications have been shown to contribute to RA-induced muscle weakness in animal models of arthritis and patients with RA. However, it is still unclear how and which sources of reactive oxygen and nitrogen species (ROS/RNS) that are involved in the oxidative stress that drives the progression toward decreased muscle function in RA. Nevertheless, mitochondria, NADPH oxidases (NOX), nitric oxide synthases (NOS) and phospholipases (PLA) have all been associated with increased ROS/RNS production in RA-induced muscle weakness. In this review, we aim to cover potential ROS sources and underlying mechanisms of oxidative stress and loss of force production in RA. We also addressed the use of antioxidants and exercise as potential tools to counteract oxidative stress and skeletal muscle weakness.

Keywords: muscle weakness; oxidative stress; reactive oxygen species; rheumatoid arthritis; skeletal muscle.

Figure 1. Excitation-contraction coupling (ECC)

ECC starts with an action potential that reaches the sarcolemma and continues down the t-tubular system of the muscle where it depolarizes and thus activates the dihypropyridine receptors (DHPR/Cav1.1). Activated DHPR mechanically interacts with RyR1 in the SR membrane. The interaction results in RyR1 activation and Ca²⁺ release from SR. Elevated Ca²⁺ levels in the myoplasm enable actin and myosin binding that leads to force production. Upon relaxation, Ca²⁺ is pumped back into the SR through the SR Ca²⁺ ATPase (SERCA, not shown in this figure).

Figure 2. Mitochondria produce O₂^•- and H₂O₂ which can contribute to the onset of oxidative stress in the muscle

RA patients have increased circulating levels of inflammatory cytokines (e.g. IFNy, TNFα and HMGB1) which can induce ROS production. Binding of HMGB1 to toll-like receptors (TLR) located on the surface membrane can lead to mitochondrial ROS production. O₂^•- is converted to H₂O₂ by superoxide dismutase (SOD, not shown here). H₂O₂ can pass through membranes of the mitochondrion and thus may elicit extra-mitochondrial oxidative stress on essential proteins for force production.

Figure 3. NOX redox signaling and tentative pathways for NOX-induced oxidative stress and muscle weakness

RA patients have increased circulating levels of inflammatory cells (e.g. monocytes) that can release pro-inflammatory cytokines such as IL-1β and TNF-α that can activate NOX. Phosphorylation of cytosolic p47^phox leads to translocation together with its associated complexes (e.g. p67^phox and p40^phox, here not shown) to the p22^phox complex, which induces O₂^•- production which is rapidly converted to H₂O₂. NOX4 is also located in the SR membrane in close proximity to RyR1.

Figure 4. PLA2 redox signaling and the possible pathways that may lead to oxidative stress

PLA2 activity can lead to O₂^•- and MDA proudction which may contribute to the onset of oxidative stress and thereby contribute to muscle weakness for patients with RA. Activation of TLR receptors and IL-1β on the surface membrane can stimulate PLA2 activity. PLA2 activation is thought to be regulated by phosphorylation induced of MAP kinase.

Figure 5. NOS redox signaling and the possible pathways that may lead to oxidative stress by induced NOS

Increased circulating levels of pro-inflammatory cytokines such TNF-α have been shown to induce nNOS activity which has been linked to muscle weakness in patients with RA. The enzyme nNOS is located among other in at the sarcolemma, the membrane of the sarcoplasmic reticulum and in the cytosol of the muscles. It can produce ROS such as O₂^−• and ONOO^−• which under oxidative stress conditions may contribute to oxidative damage on amongst others RyR1. Increased oxidative stress on the RyR1 complex mediated by nNOS has been associated with arthritis-induced muscle weakness in rodents with arthritis.