Skeletal muscle function: Role of ionic changes in fatigue, damage and disease

1. Repeated activity of skeletal muscle causes a variety of changes in its properties: muscles become weaker with intense use (fatigue), may feel sore and weak after repeated contractions involving stretch and can degenerate in some disease conditions. The present review considers the role of early ionic changes in the development of each of these conditions. 2. Single fibre preparations of mouse muscle were used to measure ionic changes following activity induced changes in function. Single fibres were dissected with intact tendons and stimulated to produce force. Fluorescent indicators were microinjected into the fibres to allow simultaneous ionic measurements with determination of mechanical performance. 3. One theory to explain muscle fatigue is that fatigue is caused by the accumulation of lactic acid, producing an intracellular acidosis that inhibits the myofibrillar proteins. In contrast, we found that during repeated tetani there was little or no pH change, but that failure of calcium release was a major contributor to fatigue. Currently, it is proposed that precipitation of calcium and phosphate in the sarcoplasmic reticulum contributes to the failure of calcium release. 4. Muscles can be used to shorten and produce force or they can be used to de-accelerate loads (stretched or eccentric contractions). One day after intense exercise involving stretched contractions, muscles are weak, sore and tender, and this damage can take a week to recover. In this condition, sarcomeres are disorganized and there are increases in resting intracellular Ca2+ and Na+. Recently, we demonstrated that the elevation of Na+ occurs through a stretch-activated channel that can be blocked by either gadolinium or streptomycin. Preventing the increase in [Na+](i) with gadolinium also prevented part of the muscle weakness after stretched contractions. 5. Duchenne muscular dystrophy is a lethal degenerative disease of muscles in which the protein dystrophin is absent. Dystrophic muscles are more susceptible to stretch-induced muscle damage and the stretch-activated channel seems to be one pathway for the increases in intracellular Ca2+ and Na+ that are a feature of this disease. We have shown recently that blockers of the stretch-activated channel can minimize some of the short-term damage in muscles from the mdx mouse, which also lacks dystrophin. Currently, we are testing whether blockers of the stretch-activated channels given systemically to mdx mice can protect against some features of the disease.