Inflammation in cases of muscle soreness?
Muscular activity, particularly unaccustomed, eccentric muscle actions (stretching of contracted muscles), can lead to damage to myofibrils and sarcomeres (2), (4–6). The damage is visible under the electron microscope immediately after the muscular activity, but may become more extensive over subsequent days. In rare cases, it may take many weeks for the muscles to regenerate (see rhabdomyolysis below). Structural damage to the contractile apparatus, cytoskeleton and cell membrane leads to both reduced muscle function and apparently a local sterile inflammation (2; see Figure 1). Human studies of radiolabelled neutrophilic granulocytes, and the detection of these cells and of monocytes/macrophages in biopsies of stressed muscle tissue, have confirmed that an inflammatory response may accompany muscle soreness. Leukocytes may be present inside capillaries and between muscle cells, while macrophages may sometimes be found inside the muscle cells (7–9).
Notably, however, the presence of leukocytes and muscle soreness did not follow the same time course. Leukocytes were first detected in the muscle tissue 48 hours after activity, whereas muscle soreness was already well-established after 24 hours – and was often in decline when levels of inflammatory cells in the muscle tissue were highest, i.e. 4–7 days after activity. In addition, it was possible for subjects with severe soreness to have very few or no signs of an inflammatory response in the muscles, and for others with strong signs of inflammation to report little soreness (7, 8). Moreover, no causal relationship has been established between muscle soreness and 'classic' cytokines such as interleukin-6 and TNF-α in human studies (2).
In a study (7) in which subjects were given a COX-2 inhibitor (celecoxib), muscle soreness was reduced but the drug did not affect the accumulation of inflammatory cells. Since celecoxib also had no effect on prostaglandin levels in the muscle interstitial fluid (measured by microdialysis), it is possible that it suppresses soreness via direct effects on the peripheral or central nervous system.
Animal models have provided evidence regarding the mechanisms underlying muscle soreness. Mizumura & Taguchi (3) summarise a number of studies performed on rats, which have approximately the same time course of soreness as humans. Rats cannot report how sore they are, but it is possible to measure how much mechanical pressure must be applied to the muscles before a rat withdraws its leg. This method has been validated in several ways, but it is important to remember that animal models can be misleading.
Mizumura & Taguchi (3) propose that muscle soreness is initiated by the formation of bradykinin (Figure 1). This vasodilatory polypeptide is a known inflammatory mediator and can activate nociceptors. Bradykinin is released during muscular activity and binds to the B2 bradykinin receptor present on muscle cells. This bradykinin activity stimulates increased synthesis of nerve growth factor (NGF) mRNA as well as ensuing protein synthesis, which is thought to occur inside muscle and satellite cells (muscle stem cells). The time required to produce nerve growth factor could potentially explain the delayed onset of muscle soreness. The growth factor can sensitise C-fibres and give rise to pressure hyperalgesia, which is typical of muscle soreness. However, bradykinin and nerve growth factor do not appear to be alone in causing soreness. Increased presence of glial cell line-derived neurotrophic factor (GDNF) induced by prostaglandin E2 upon stimulation of COX-2 activity may also contribute to hyperalgesia (Aδ fibres). The nociceptors that mediate muscle soreness in response to nerve growth factor and glial cell line-derived neurotrophic factor, thus appear to be the standard C and Aδ fibres. Since both bradykinin and prostaglandin E2 can be produced locally in the muscle and have autocrine and paracrine effects, muscle soreness does not appear to be dependent on inflammatory cells. This lends support to the results of the human studies described above: muscle soreness is not normally due to classic tissue inflammation.
It is worth noting that the processes described occur in the vicinity of capillaries and nerve endings in the extracellular matrix and connective tissue – not intracellularly, even though a number of the mediators are produced there (Figure 1). We therefore believe that muscle soreness is not directly related to intracellular muscle damage. However, we cannot exclude the possibility that some form of damage to the muscle connective tissue contributes to muscle soreness, as suggested by Abraham back in 1977 (10).