Track topics on Twitter Track topics that are important to you
A major contributor to frailty and immobility in the elderly is the age related loss of muscle mass (sarcopenia). Cardiovascular disease (CVD) is the leading cause of mortality in the elderly, with high blood cholesterol and lipids being the major modifiable risk factor. Statins reduce blood cholesterol, but muscle related pain, tenderness and discomfort (myopathy) is an adverse event associated with statin therapy, with older people being at a much greater risk. Statin myopathy presents as muscle aches and weakness, with or without evidence of muscle damage; however the underlying mechanisms responsible for these symptoms are poorly understood. Using an animal model, the applicants have shown the main pathway regulating muscle protein synthesis is inhibited in statin myopathy, and genes regulating muscle protein breakdown, the inhibition of muscle carbohydrate use and inflammation are dramatically increased. Therefore we wish to determine whether these changes are seen in the muscle of older people with symptoms of statin myopathy, and whether this is associated with lower muscle mass and impaired muscle function compared with older people with no history of statin use. Identification of the mechanisms involved in statin myopathy could lead to effective therapy for older people unable to tolerate statins.
Cardiovascular disease is the leading cause of mortality in elderly people accounting for >208,000 deaths each year, with hyperlipidaemia being the major modifiable risk factor in the elderly. Statins inhibit synthesis of cholesterol, and their therapy has been associated with a 30% reduction in cardiovascular events. Statins are generally well tolerated, but can have myopathic effects. Randomised trials suggest rhabdomyolysis (> 10 times the upper limit of normal serum creatine kinase (CK)) is rare, and even myalgia and myositis (muscle aches or weaknesses with and without increases in serum CK, respectively), although more common, are not highly prevalent. However, the incidence of adverse muscular events associated with the most commonly prescribed statin, simvastatin, is high, particularly at high doses (18%), and given the recommendation by NICE to prescribe simvastatin over other statins, adverse muscular events could potentially increase further with increased use, and particularly in the elderly who are at a far greater risk . Using an animal model, the applicants have shown that the principal pathway thought to regulate muscle protein synthesis (the PI3k/Akt signalling pathway) is down regulated in simvastatin induced myopathy . Furthermore, this was paralleled by the marked up regulation of genes thought to increase muscle protein breakdown, impair carbohydrate oxidation, and increase oxidative stress and inflammation. We will test the hypotheses: (i) That people over 65 years of age prescribed simvastatin, and experiencing muscle related aches and pains, will present with exacerbated muscle mass loss and impaired muscle function (strength and fatigability) compared to age and sex matched control volunteers (statin free). (ii) That signaling pathways and genes seen to be dysregulated in an animal model of simvastatin induced myopathy will also be dysregulated in the muscle of older people prescribed simvastatin and experiencing muscle related aches and pains, and may thereby underpin the symptoms associated with statin myopathy. We will recruit 15, male volunteers > 65 years of age reporting myopathic symptoms with simvastatin administration and 15 age and sex matched control volunteers (statin free). Volunteers will be deemed suitable for entry into a statin myopathy group if they show elevated serum CK, muscle tenderness, reduced isometric strength [for their age] and appropriate scoring of a muscle pain questionnaire. All volunteers will undertake two experimental visits: Visit 1 to determine body composition, muscle strength and fatigability, and Visit 2 to undergo an insulin clamp lasting 3 hours. Visit 1 will involve measurement of body composition using DEXA, and isometric strength and fatigability of the knee extensor muscles using an exercise dynamometer. Visit 2 will involve muscle protein synthesis, leg protein breakdown and glucose disposal being determined, using a primed constant infusion of stable isotope labeled amino acids during a two-stage 180 min insulin clamp at rest (see detailed protocol for specifics). In short, a basal muscle biopsy will be obtained (Vastus lateralis), after which serum insulin will be clamped at the fasted concentration (~5 mU/l) for the first 90 min, allowing processes that govern protein breakdown to occur without any inhibitory effect of raised serum insulin, and will be followed by a second muscle biopsy. For the remaining 90 min, serum insulin will be raised equivalent to the fed state by the administration of 30 mU.m-2.min-1 insulin, along with a variable infusion of 20% glucose to maintain plasma glucose concentration at 4.5 mmol.l-1. Also a constant infusion of mixed amino acids will be administered (10g per hour) allowing protein synthesis to be examined. Furthermore, insulin resistance will be estimated during this second 90 min by measuring leg glucose disposal. A third muscle biopsy sample will be obtained after this second 90 min period of investigation. Determination of muscle protein synthesis and leg protein breakdown will necessitate a femoral vein catheter being inserted for venous blood sampling, a cannula being inserted retrogradely into a superficial vein of a heated hand for sampling of arterialised-venous blood, and a cannula being placed in the antecubital vein of both forearms for the infusion of mixed amino acids, as well as octreotide, glucose and insulin. Femoral arterial and femoral venous blood flow will be determined using Doppler ultrasound, which is completely non-invasive. Body composition and leg isometric strength and fatigue will be determined (Visit 1). Muscle biopsy samples and blood samples will be used to determine rates of muscle protein synthesis, breakdown and glucose disposal. Muscle biopsy samples will also be used to examine the expression of genes and proteins that regulate muscle protein balance, inflammation and carbohydrate metabolism. Sample size is based on the observed increase in atrophy gene (MAFbx) expression in muscle of statin treated individuals . A 2 fold increase in MAFbx mRNA (standard deviation = 0.3 fold) was reported in muscle from 8 individuals treated with statins experiencing myopathic symptoms compared to controls. Therefore, assuming a power of 80%, 7 subjects would be required to detect an effect. Being conservative, and accounting for some drop outs, we will recruit 15 volunteers per group to ensure sufficient statistical power. There are currently no measures of muscle protein synthesis, degradation or anabolic signaling proteins in people reporting statin myopathy on which to base additional power calculations, but studies in people between 65-85 years of age in which such measurements have been made by the applicants have involved similar numbers of men and women.
Observational Model: Cohort, Time Perspective: Cross-Sectional
David Greenfield Physiology Laboratories
University of Nottingham
Published on BioPortfolio: 2014-08-27T03:16:45-0400
OBJECTIVES: I. Assess the efficacy of thioctic acid in treating a single patient with mitochondrial myopathy.
The objective of this study is to determine whether the administration of N-acetylcysteine (NAC) improves oxidative stress. To determine this, the study will assess the impact of oral tre...
This study is a longitudinal study evaluating the severity and progression of respiratory muscle function in patients with X-Linked Myotubular Myopathy (XLMTM) aged 0-14.
To observe not only the distribution of single nucleotide polymorphism in genes related with pharmacodynamic and pharmacokinetics alteration of statins but also to analyze the correlation ...
There is a significant proportion of patients complaining of muscle symptoms while on statin therapy who have a measurable difference in muscle strength or endurance and whose muscle biops...
Amyloid myopathy frequently occurs in the setting of systemic amyloidosis and less commonly in isolation (isolated amyloid myopathy). Anoctaminopathy-5 and dysferlinopathy were recently recognized as ...
Mutation in the collagen XII gene (COL12A1) was recently reported to induce Bethlem myopathy. We describe a family affected by collagen XII-related myopathy in 3 generations.
The thalassemias are the most common single gene disorder in the world. Nowadays, the average life expectancy of patients in developed countries has increased significantly, while, there was an increa...
Mutations in the small heat shock protein 22 gene (HSPB8) have been associated with Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy (dHMN) type IIa and, more recently, distal myopathy/...
Statins therapy is effective in the prevention of cardiovascular events. However, its use is associated with skeletal muscle myopathy, which may be severe enough to discontinue statin therapy, thus ex...
An X-linked dominant multisystem disorder resulting in cardiomyopathy, myopathy and MENTAL RETARDATION. It is caused by mutation in the gene encoding LYSOSOMAL-ASSOCIATED MEMBRANE PROTEIN 2.
A caveolin that is expressed exclusively in MUSCLE CELLS and is sufficient to form CAVEOLAE in SARCOLEMMA. Mutations in caveolin 3 are associated with multiple muscle diseases including DISTAL MYOPATHY and LIMB-GIRDLE MUSCULAR DYSTROPHY.
An inherited congenital myopathic condition characterized by weakness and hypotonia in infancy and delayed motor development. Muscle biopsy reveals a condensation of myofibrils and myofibrillar material in the central portion of each muscle fiber. (Adams et al., Principles of Neurology, 6th ed, p1452)
A mitochondrial encephalomyopathy characterized clinically by a mixed seizure disorder, myoclonus, progressive ataxia, spasticity, and a mild myopathy. Dysarthria, optic atrophy, growth retardation, deafness, and dementia may also occur. This condition tends to present in childhood and to be transmitted via maternal lineage. Muscle biopsies reveal ragged-red fibers and respiratory chain enzymatic defects. (From Adams et al., Principles of Neurology, 6th ed, p986)
A myodegeneration most frequent in calves and lambs whose dams have been fed during gestation or longer on feeds, especially legumes (FABACEAE), grown in certain areas where selenium is either deficient or unavailable in the soil. It has been recorded in many countries. It has been produced experimentally in several species of animals on low-selenium intake. A similar myopathy occurs naturally in goats, deer, foals, and dogs but proof of the etiology is lacking. (Merck Veterinary Manual, 5th ed)
Arthritis Fibromyalgia Gout Lupus Rheumatic Rheumatology is the medical specialty concerned with the diagnosis and management of disease involving joints, tendons, muscles, ligaments and associated structures (Oxford Medical Diction...
Cardiovascular disease (CVD)
Acute Coronary Syndromes (ACS) Blood Cardiovascular Dialysis Hypertension Stent Stroke Vascular Cardiovascular disease (CVD) includes all the diseases of the heart and circulation including coronary heart disease (angina...