Maintenance of Muscle Mass in Older People: the Negative Impact of Statin Therapy
Condition: Myopathy
MeSH terms: Muscular Diseases
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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 National Institute for Health and Care Excellence 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 [1]. Using
      an animal model, the applicants have shown that the principal pathway thought to regulate
      muscle protein synthesis (the phosphatidylinositol 3-kinase/Protein Kinase B (PI3k/Akt)
      signalling pathway) is down regulated in simvastatin induced myopathy [2]. 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
      dual energy X-ray absorptiometry (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 milliunit (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 retrograde 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 [3]. A 2 fold increase in MAFbx messenger ribonucleic acid (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
Sampling method: Non-Probability Sample
Study population: 
        Community Sample
      
Biospecimen description: 
      Plasma, Muscle biopsy, Serum & Whole blood
    
Keywords: Muscle soreness; Simvastatin; Men; Muscle Atrophy