Excitation‐induced Ca²⁺ influx and skeletal muscle cell damage

Abstract

Excessive exercise may lead to skeletal muscle cell damage with degradation of cellular components and leakage of intracellular enzymes. Calcium has repeatedly been proposed to be involved in these processes. Studies have shown that the resting level of cytoplasmic Ca2+ increases up to threefold during long-term low-frequency stimulation. We have shown that electrical stimulation produces a marked increase in Ca2+ uptake and Ca2+ content in rat skeletal muscle, both in vivo and in vitro. Continuous stimulation for 240 min at 1 Hz results in an increased release (18-fold) of lactate dehydrogenase (LDH) from extensor digitorum longus (EDL) muscle. This was associated with an increased total Ca2+ content (185%), was augmented at high [Ca2+]o and suppressed at low [Ca2+]o. The release of LDH may reflect partial loss of sarcolemmal integrity as a result of degradation of membrane components by Ca2+-activated enzymes (e.g. calpain or phospholipase A2). After cessation of stimulation the increased release of LDH continues for at least 120 min. This is associated with an up to sevenfold increase in 45Ca uptake. The increased permeability to Ca2+ may further activate calpain and phospholipase A2 and accelerate the loss of membrane integrity. Stimulation-induced uptake of Ca2+ and release of LDH is most pronounced in EDL (mainly composed of fast-twitch fibres at variance with soleus which is mainly composed of slow-twitch fibres). This may account for the observation that prolonged exercise leads to preferential damage to fast-twitch fibres. We hypothesize that excessive exercise may lead to an intracellular accumulation of Ca2+ and increased cytoplasmic Ca2+ causing activation of self-accelerating degradative pathways leading to muscle damage.

Ca2+ uptake and cellular integrity in rat EDL muscle exposed to electrostimulation, electroporation, or A23187

“…The present observations confirm and extend previous studies (17,20,21) in documenting that Ca 2ϩ gaining access to the cytoplasm from the extracellular phase elicits loss of cellular integrity. The new aspect is that this process seems to be self-increasing, which possibly leads to more extensive muscle damage.…”

The efficacy of protein supplementation during recovery from muscle-damaging concurrent exercise

“…This increase in 'leakage' of intramuscular proteins into the bloodstream is just one of the events that are observed following EIMD, which appear as part of the cascade of events following the disruption of the intracellular Ca 2+ homeostasis (Gissel and Clausen, 2001). The increased CRP values, which peaked at 24 h, suggest that the exercise stimulus was also sufficient to elicit an inflammatory response.…”

Intracellular calcium accumulation following eccentric contractions in rat skeletal muscle in vivo: role of stretch-activated channels

“…It is well known that eccentric (ECC) contractions induce muscle damage (8,26,44), and it has been suggested that one principal cause of that damage is high [Ca 2ϩ ] i (1,17). Moreover, if ECC does cause increased [Ca 2ϩ ] i , it is possible that stretch-activated ion channels (SAC) are involved in this response (1, 54 -56) and the associated muscle damage.…”