Defective Membrane Systems in Dystrophic Skeletal Muscle of the UM-X7.1 Strain of Genetically Myopathic Hamster

Abstract

1. The function of mitochondria, sarcotubular membranes (heavy microsomes), sarcolemma and myofibrils from the hind-leg skeletal muscle of about 60- and 150-day-old normal and myopathic (UM-X7.1) hamsters was examined. 2. The mitochondrial calcium uptake as well as mitochondrial phosphorylation and respiratory rates were lower in 60-day-old myopathic skeletal muscle, unlike 150-day-old myopathic animals, when pyruvate-malate and glutamate-malate were used as substrates. However, mitochondria from 150-day-old myopathic animals showed depressed glutamate-dependent respiratory and phosphorylation rates and succinate-supported initial rate of calcium uptake. 3. The microsomal calcium-uptake, but not calcium-binding, and Ca2+-stimulated adenosine triphosphatase (ATPase) activity of the 150-day-old myopathic skeletal muscle were lower than the control values. Although microsomal calcium-binding, calcium-uptake and ATPase activities of the 60-day-old myopathic muscle were not depressed significantly, the initial rate of calcium uptake was less than the control. 4. The sarcolemmal Ca2+-ATPase, but not Mg2+-ATPase or Na+ +K+-ATPase, activity was higher in 60-day-old myopathic muscle whereas the activities of all these enzymes from 150-day-old myopathic animals were higher than the control. On the other hand, the Na+ +K+-ATPase activities from 60- and 150-day-old myopathic animals were inhibited by ouabain to a lesser extent in comparison with the respective control values. 5. The myofibrillar Ca2+-ATPase and Mg2+-ATPase activities as well as inhibition of Mg2+-ATPase due to Na+ and K+ in myopathic muscle were no different from the control values. 6. The results reported here give further support to the view that different membrane systems of the dystrophic muscle are defective.

Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles

“…Ultrastructural examination of dystrophic muscle revealed segmental fiber breakdown and Ca 2+ -deposits in myocytes with intact basement membrane as significant features [65,66,[70][71][72]. Several changes indicating biochemical abnormalities in the sarcolemma (SL) membrane were observed in differ-ent types of dystrophic muscle [73][74][75][76]. Marked alterations in lipid and electrolyte content were also seen in dystrophic muscle indicating abnormal function of the cell for maintaining appropriate levels of intracellular components [73,77].…”

“…Alterations in the integrity of dystrophic muscle membrane [79,80] were associated with changes in different SL enzyme systems such as Na + -K + ATPase, Ca 2+ /Mg 2+ ecto-ATPase, and adenylyl cyclase [74][75][76][81][82][83][84][85]. Since both cholesterol and phospholipids are known to exert membrane stabilizing effects [86,87] and the ratio of cholesterol/phospholipids was elevated in dystrophic muscle [88], it has been suggested that the observed changes in enzyme activities are a consequence of alterations in the SL lipid composition.…”

“…Studies from dystrophic muscle fibroblasts and skin fibroblast cultures have also shown different alterations such as cytoplasmic inclusion bodies, defective collagen incorporation as well as membrane defects [89][90][91][92][93]. Furthermore, derangements in the function of intracellular membrane systems such as the sarcoplasmic reticulum (SR) [40,76,88] and mitochondria [41,76,[94][95][96] were reported in dystrophic muscle. Although no alterations in myofibrillar ATPase activity and contractile proteins in myopathic hamster muscle were observed [30,76], some investigators have shown defective myosin in a chicken model of muscular dystrophy [97].…”

Isradipine prevents the development of spontaneously occurring cardiac necrosis in cardiomyopathic hamster

“…Cardiomyopathy in hamsters develops in a phasic pattern with well-defined and predictable stages: 1, a necrotic phase with disseminated lesions in the myocardium elapsing between 30 and 120 days; 2, a healing phase characterized by a scarring process with ventricular hypertrophy and dilatation until 200 days of age; 3, a terminal phase with typical changes of heart failure until death occurs near 250 days (Dhalla et al 1975).…”

Incorporation of amino acids into soluble and membrane protein fractions of dystrophic hamsters

“…Changes in membrane function have been reported in dystrophic hamsters (Sulakhe et al, 1971;Mezon et al, 1974;Dhalla et al, 1975), as well as in dystrophic mice, in dystrophic chickens and in humans with Duchenne dystrophy (see, e.g., Mawatari et al, 1976';, Wrogemann & Pena, 1976; * To whom reprint requiiests should be addressed. Howland & Iyer, 1977;Duncan, 1978;de Kretser & Livett, 1977;Mrak & Baskin, 1978;Rodan et al, 1974;Sabbadini et al, 1975;Louie & Peck, 1979).…”