Abstract
McArdle disease is caused by lack of glycogen phosphorylase (GP) activity in skeletal muscle. Patients experience exercise intolerance, presenting as early fatigue and contractures. In this study, we investigated the effects produced by a lack of GP on several genes and proteins of skeletal muscle in McArdle patients. Muscle tissue of 35 patients and 7 healthy controls were used to identify abnormalities in the patients' transcriptomic profile using low-density arrays. Gene expression was analyzed for the influence of variables such as sex and clinical severity. Differences in protein expression were studied by immunoblotting and 2D electrophoresis analysis, and protein complexes were examined by two-dimensional, blue native gel electrophoresis (BN-PAGE). A number of genes including those encoding acetyl-coA carboxylase beta, m-cadherin, calpain III, creatine kinase, glycogen synthase (GS), and sarcoplasmic reticulum calcium ATPase 1 (SERCA1), were found to be downregulated in patients. Specifically, compared to controls, GS and SERCA1 proteins were reduced by 50% and 75% respectively; also, unphosphorylated GS and SERCA1 were highly downregulated. On BN-PAGE analysis, GP was present with GS in two muscle protein complexes. Our findings revealed some issues that could be important in understanding the physiological consequences of McArdle disease: (i) SERCA1 downregulation in patients could result in impaired calcium transport in type II (fast-twitch) muscle fibers, leading to early fatigability during exercise tasks involving type II fibers (which mostly use glycolytic metabolism), i.e. isometric exercise, lifting weights or intense dynamic exercise (stair climbing, bicycling, walking at a very brisk pace), (ii) GP and GS were found together in two protein complexes, which suggests a new regulatory mechanism in the activity of these glycogen enzymes.
Highlights
McArdle disease is an autosomal recessive disorder caused by a deficiency of muscle glycogen phosphorylase (GP), the enzyme that catalyzes the first step in glycogen catabolism [1,2]
Amongst the 16 genes whose transcripts levels were found to be significantly lower compared with controls, we found both GYS1 and SERCA1 genes which we decided to analyse at their protein level due to their well-known key role in muscle function
Skeletal muscle is the major site of insulin-stimulated glucose uptake, and most of this glucose is stored as glycogen through glycogen synthase (GS) activity [21]
Summary
McArdle disease (glycogen storage disease type V) is an autosomal recessive disorder caused by a deficiency of muscle glycogen phosphorylase (GP), the enzyme that catalyzes the first step in glycogen catabolism [1,2]. Because of this deficiency, daily life activities involving isometric exercise (e.g. lifting weights) or dynamic exercise (e.g. stair climbing) trigger exercise intolerance in McArdle patients, which manifests as early fatigue and contractures, sometimes accompanied by rhabdomyolysis and myoglobinuria [3]. The premature muscle fatigue and cramping of McArdle patients is associated with an increased accumulation of Pi and probably ADP in skeletal muscle; accumulations of Pi and ADP are known to inhibit (i) myofibrillar, (ii) sarcoplasmic reticulum (SR) Ca2+, and (iii) membrane Na+-K+-ATPase reactions
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