Statin myalgia is not associated with reduced muscle strength, mass or protein turnover in older male volunteers, but is allied with a slowing of time to peak power output, insulin resistance and differential muscle mRNA expression

Abstract

Statins are associated with muscle myalgia and myopathy, which probably reduce habitual physical activity. This is particularly relevant to older people who are less active, sarcopaenic and at increased risk of statin myalgia. We hypothesised that statin myalgia would be allied to impaired strength and work capacity in older people, and determined whether differences aligned with divergences in lean mass, protein turnover, insulin sensitivity and the molecular regulation of these processes. Knee extensor strength and work output during 30 maximal isokinetic contractions were assessed in healthy male volunteers, nine with no statin use (control 70.4 ± 0.7 years) and nine with statin myalgia (71.5 ± 0.9 years). Whole body and leg glucose disposal, muscle myofibrillar protein synthesis (MPS) and leg protein breakdown (LPB) were measured during fasting (≈5 mU l(-1) insulin) and fed (≈40 mU l(-1) insulin + hyperaminoacidaemia) euglyceamic clamps. Muscle biopsies were taken before and after each clamp. Lean mass, MPS, LPB and strength were not different but work output during the initial three isokinetic contractions was 19% lower (P < 0.05) in statin myalgic subjects due to a delay in time to reach peak power output. Statin myalgic subjects had reduced whole body (P = 0.05) and leg (P < 0.01) glucose disposal, greater abdominal adiposity (P < 0.05) and differential expression of 33 muscle mRNAs (5% false discovery rate (FDR)), six of which, linked to mitochondrial dysfunction and apoptosis, increased at 1% FDR. Statin myalgia was associated with impaired muscle function, increased abdominal adiposity, whole body and leg insulin resistance, and evidence of mitochondrial dysfunction and apoptosis.

© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Figures

Figure 1. Study protocol

Primed constant infusions of stable isotope‐labelled AAs ([2H5]phenylalanine and [1,2‐13C] leucine) were administered for a total period of 240 min. Serum insulin was maintained at fasting concentrations (≈5 mU l−1) for 120 min and endogenous insulin production was suppressed by infusion of octreotide, and post‐absorptive glucagon concentration was maintained by infusion of glucagon. After 120 min, serum insulin was raised equivalent to a fed state (≈40 mU l−1). Quadriceps muscle biopsies were taken at baseline, 120 min and 240 min.

Figure 2. Body composition of control and statin user groups

Values are expressed as mean ± SEM. *P < 0.05 when comparing arm fat mass, and †P < 0.05 when comparing trunk fat mass between control and statin myalgic subjects.

Figure 3. Muscle functional measurements in control and statin user groups

A, isometric strength (kg kg leg lean mass−1); B, peak power output (W kg leg lean mass−1); C, peak isokinetic work per contraction (Nm) during 30 maximal isokinetic contractions. Values are expressed as mean ± SEM. *P < 0.05 compared to control.

Figure 4. Serum insulin concentration and blood glucose disposal rate in control and statin user groups

A, serum insulin area under the curve (AUC) (μIU ml−1 min−1) during the period of steady‐state glucose disposal of the fed state clamp (40 mU m−2 min−1 insulin and 10 g h−1 mixed amino acids); B, rate of steady‐state whole body glucose disposal (mg kg−1 min−1) during the fed state clamp; C, rate of steady‐state leg glucose uptake during the fed state clamp (mg kg−1 leg lean mass min−1); D, relationship between whole body glucose disposal (mg kg−1 min−1) and trunk fat mass (kg). Closed circles = control, open circles = statin myalgic subjects. All values are expressed as mean ± SEM. **P < 0.01 compared to control.

Figure 5. Muscle protein synthesis and leg protein breakdown in control and statin user groups

A, rate of muscle protein synthesis (fractional synthetic rate, FSR) during a 2 h fasted state insulin clamp (0.6 mU m−2 min−1 insulin) and a 2 h fed state insulin clamp (40 mU m−2 min−1 insulin and 10 g h−1 mixed AAs); B, rate of leg protein breakdown during a 2 h fasted state and a 2 h fed state insulin clamp. Values are expressed as mean ± SEM. ***P < 0.001 when fasted vs. fed clamp.

Figure 6. Expression levels of proteins involved in translation initiation of muscle protein synthesis in skeletal muscle in control and statin user groups

A, ratio of muscle phosphorylated to total p70S6k protein expression; and B, ratio of muscle phosphorylated to total 4EBP1 protein expression. *P < 0.05 compared to control within the fed state clamp. Values are expressed as mean intensity (normalised to β‐actin) ± SEM.

Figure 7. Muscle mRNA expression normalised to HMBS in the statin user group relative to control at baseline (fold change)

A–E, SAM analysis, using an FDR of 5%, revealed these genes to be significantly up‐regulated in statin myalgic subjects. Values are expressed as mean ± SEM. Control values are set at 1 and are represented as a dotted line. F, muscle creatine kinase mRNA expression normalised to HMBS (fold change relative to control). Values are expressed as mean ± SEM (black horizontal bar) and individual fold difference in statin myalgic subjects (black spots). ***P < 0.001 when compared to control.