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Applied exercise physiology and health
Published in Nick Draper, Helen Marshall, Exercise Physiology, 2014
An interesting health issue, from an exercise physiological perspective that relates to glycolysis as was covered in Chapter 10, is the occurrence of McArdle disease. McArdle disease was first reported in 1951 by a London doctor, Dr Brian McArdle, after he assessed the symptoms of a patient and diagnosed a problem relating to glycogen breakdown. His tests also revealed that his patient did not accumulate lactate during anaerobic exercise. The disease, also known as glycogen storage disease type V, is thought to affect around 1 in 100,000 people although only about one-third are diagnosed. It was later discovered that the problem with glycogen breakdown related to an enzyme deficiency, specifically, glycogen phosphorylase. As can be seen from Figure 10.3 (in Chapter 10), glycogen phosphorylase, also known as myophosphorylase, catalyses and regulates the breakdown of glycogen to glycogen-1-phosphate-2. Patients have symptoms from childhood but it is common for the disease not to be correctly diagnosed until adulthood. This was the case for the person who wrote the following blog extract.
New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia
Published in Expert Opinion on Investigational Drugs, 2019
The results obtained testing HDAC inhibitors in experimental models of muscle wasting have led, so far, to only two registered clinical trials in the http://clinicaltrials.gov platform, one testing valproate and levocarnitine in children with spinal muscular atrophy (NCT01671384), having changes in muscle force as primary outcome, change in forced vital capacity and valproate side effects as secondary outcomes and the other administering sodium valproate for glycogen storage disease type V (NCT03112889), with changes in VO2 peak as primary outcome and presence of phosphorylase positive fibers, change in total walked distance (12 min walk), blood lactate and quality of life as secondary outcomes. Of these trials, the former appears still recruiting subjects, while the latter has been completed in February 2018 and not yet published. The limited translation of experimental results into clinical trials likely reflects the lack of solid evidences of HDAC inhibitor effectiveness in preventing/delaying the onset of cachexia.
Multimodal imaging of posterior ocular involvement in McArdle's disease
Published in Clinical and Experimental Optometry, 2018
Giuseppe Casalino, Wing Chan, Clara Mcavoy, Michele Coppola, Francesco Bandello, Alan C Bird, Usha Chakravarthy
McArdle's disease is an extremely rare glycogen storage disease (type V), first reported by Brian McArdle in 1951.1951 This condition is characterised by rapid fatigue, myalgia and cramps in exercising muscles.2010 Manifestations of McArdle's disease are a direct result of deficiency of myophosphorylase function. Without this enzyme, the glycogenolysis pathway cannot adequately provide energy in the form of adenosine triphosphate for the maintenance of strenuous activity.2010 Homozygous or compound heterozygous mutations in the myophosphorylase gene, located on chromosome 11, are the cause of the deficiency of myophosphorylase function.2010
An overview of statin-induced myopathy and perspectives for the future
Published in Expert Opinion on Drug Safety, 2020
Dragana Nikolic, Maciej Banach, Roberta Chianetta, Luca Marco Luzzu, Anca Pantea Stoian, Camelia Cristina Diaconu, Roberto Citarrella, Giuseppe Montalto, Manfredi Rizzo
Genetic variants were used to identify factors contributing to the SAMS suggesting that some subjects are prone to statin intolerance/statin myopathy due to preexisting inherited muscular disorders, or genetic variation in statin uptake proteins encoded by solute carrier organic anion transporter family member 1B1 (SLCO1B1) or the cytochrome P (CYP) enzyme system [39]. It has been demonstrated that hereditary metabolic diseases are not rare among subjects with drug-induced myopathies and that carrier status alone for either McArdle disease (glycogen storage disease type V) or carnitine palmitoyltransferase (CPT) II deficiency may be associated with an increased risk for myopathic outcomes [40]. Pathogenic variants in the genes causative for malignant hyperthermia (ryanodine receptor 1 (RYR1) and calcium voltage-gated channel subunit alpha1 S (CACNA1 S)) were found to be significant potential contributors to risk for severe SAMS [41]. Besides, variations in genes affecting polymorphisms in vascular receptors and pain perception may also contribute to SAMS. It is known that statin-associated AEs might be associated with polymorphisms in several key genes coding for transporters and metabolizing enzymes that affect statin pharmacokinetics. The association between the risk of myopathy with cytochrome P450 3A5*3(CYP3A5*3) T > C (rs776746), COQ G > C (rs4693075), and SLCO1B1 T > C (rs4149056) genetic variants were investigated in South Indian patients on statins and the results clearly demonstrate that the frequency of CYP3A5*3 splicing variant is higher in myopathy group than in the tolerant group, while a significant association of genetic polymorphisms in CYP3A5, COQ, and SLCO1B1 with atorvastatin- or rosuvastatin-induced myopathy was not found [42]. The SLCO1B1 521 T > C and 388A>G polymorphisms are commonly occurring variants in ethnically diverse populations, and numerous in vitro and clinical studies have investigated the consequences of these variants to interindividual differences in drug disposition and response [43]. The potent inhibition of human organic anion transporting polypeptide 1B1 (OATP1B1)/OATP1B3 by fusidic acid could attenuate hepatic uptake of statins, resulting in increased blood and tissue concentrations, potentially manifesting in musculoskeletal toxicity [44]. SLCO1B1 T521 C was associated with a higher risk of SAMS, especially for simvastatin, rosuvastatin, and cerivastatin [45]. Future studies should be performed, including subjects receiving specific types of drugs, and any potential adverse events need to be explored.