Muscle Weakness in Rheumatoid Arthritis: The Role of Ca2+ and Free Radical Signaling

Abstract

In addition to the primary symptoms arising from inflammatory processes in the joints, muscle weakness is commonly reported by patients with rheumatoid arthritis (RA). Muscle weakness not only reduces the quality of life for the affected patients, but also dramatically increases the burden on society since patients' work ability decreases. A 25-70% reduction in muscular strength has been observed in pateints with RA when compared with age-matched healthy controls. The reduction in muscle strength is often larger than what could be explained by the reduction in muscle size in patients with RA, which indicates that intracellular (intrinsic) muscle dysfunction plays an important role in the underlying mechanism of muscle weakness associated with RA. In this review, we highlight the present understanding of RA-associated muscle weakness with special focus on how enhanced Ca²⁺ release from the ryanodine receptor and free radicals (reactive oxygen/nitrogen species) contributes to muscle weakness, and recent developments of novel therapeutic interventions.

Keywords: Ca(2+); Muscle weakness; Nitrosative stress; Peroxynitrite; Rheumatoid arthritis; Ryanodine receptor.

Fig. 1

Illustration of the intracellular events leading to contraction of skeletal muscle fibers. The dihydropyridine receptor (DHPR or Cav_1.1) is voltage-sensite and activated by actionpotentials (1). The DHPR opens RyR1 by mechanical interaction resulting in release of Ca^2 + (2) from the sarcoplasmic reticulum (SR) and a transient increase in intracellular (myoplasmic) Ca^2 + (~ 1–5 μM). Ca^2 + binds to the troponin complex (3), which moves the position of the tropomyosin filaments. This uncovers the active sites of actin for myosin binding (4), which enables actin and myosin interaction and force production. The SR Ca^2 + ATPase (Serca) pumps Ca^2 + back into SR (5) and [Ca^2 +]_i returns to resting levels and the contraction ceases. At rest, when the intracellular Ca^2 + concentration is low (~ 50 nM), the tropomyosin filaments hide the myosin binding sites on actin (6), hence no force can be produced.

Fig. 2

Increased tetanic Ca^2 + accompanied by muscle weakness in muscle fibers from mice with RA (collagen-induced arthritis, CIA). (A) The intracellular Ca^2 + concentration ([Ca^2 +]_i) was significantly increased over a wide range of stimulation frequencies in muscle fibers from RA mice (red circles) compared with controls (white circles). (B) The increased tetanic Ca^2 + was accompanied by decreased force per cross-sectional area in muscle fibers from mice with RA (n = 9–10). Single intact flexor digitorium brevis (FDB) fibers (fast-twitch, type II) were used for this set of experiements. The FDB fibers were obtained by dissection and mounted in a chamber between a force transducer and an adjustable holder. The fibre length was adjusted to obtain maximum tetanic force. The diameter of the fibre at this length was used to calculate the cross-sectional area. Experiments were performed at room temperature (∼ 24 °C). The fibre was stimulated with supramaximal electrical pulses (0.5 ms in duration, 1–120 Hz) delivered via platinum electrodes placed along the long axis of the fibre. [Ca^2 +]_i was measured with the fluorescent Ca^2 + indicator indo-1. Indo-1 was microinjected into the isolated fibre, which was then allowed to rest for at least 20 min. The mean fluorescence of indo-1 at rest and during tetanic contractions was measured and converted to [Ca^2 +]_i using an intracellularly established calibration curve (Andrade et al., 1998). Data are mean ± SEM; *p < 0.05; **p < 0.01; ***p < 0.001 versus controls.

Fig. 3

ROS/RNS sources and the tentative vicious cycle in RA-associated muscle weakness. Summary of potential sources to O₂^•−, NO and ONOO^•− in RA muscles, including NOS1, NOX2, and mitochondria. This model suggests that NOS1 is globally increased and more NOS1 is bound to the RyR1 protein complex in arthritic muscle than in control muscle (1). This leads to ONOO^•−-induced modifications of the RyR1 protein complex and the SR Ca^2 + release during contractions increases, which further activates the Ca^2 +-sensitive NOS1 and amplifies the ROS/RNS production (2). The increased amounts of ONOO^•− attack myofibrillar proteins, e.g. actin (3), which results in contractile dysfunction and muscle weakness.