Statins Affect Skeletal Muscle Performance

Evidence for Disturbances in Energy Metabolism

Neeltje A. E. Allard; Tom J. J. Schirris; Rebecca J. Verheggen; Frans G. M. Russel; Richard J. Rodenburg; Jan A. M. Smeitink; Paul D. Thompson; Maria T. E. Hopman; Silvie Timmers

Disclosures

J Clin Endocrinol Metab. 2018;103(1):75-84.

Abstract and Introduction

Abstract

Context: Statin myopathy is linked to disturbances in mitochondrial function and exercise intolerance.

Objectives: To determine whether differences exist in exercise performance, muscle function, and muscle mitochondrial oxidative capacity and content between symptomatic and asymptomatic statin users, and control subjects.

Design: Cross-sectional study.

Setting: Department of Physiology, Radboud University Medical Center.

Participants: Long-term symptomatic and asymptomatic statin users, and control subjects (n = 10 per group).

Interventions: Maximal incremental cycling tests, involuntary electrically stimulated isometric quadriceps-muscle contractions, and biopsy of vastus lateralis muscle.

Main Outcomes Measured: Maximal exercise capacity, substrate use during exercise, muscle function, and mitochondrial energy metabolism.

Results: Peak oxygen uptake, maximal work load, and ventilatory efficiency were comparable between groups, but both statin groups had a depressed anaerobic threshold compared with the control group (P = 0.01). Muscle relaxation time was prolonged in both statin groups compared with the control group and rate of maximal force rise was decreased (P _time×group < 0.001 for both measures). Mitochondrial activity of complexes II and IV was lower in symptomatic statin users than control subjects and tended to be lower for complex (C) III (CII: P = 0.03; CIII: P = 0.05; CIV: P = 0.04). Mitochondrial content tended to be lower in both statin groups than in control subjects.

Conclusion: Statin use attenuated substrate use during maximal exercise performance, induced muscle fatigue during repeated muscle contractions, and decreased muscle mitochondrial oxidative capacity. This suggests disturbances in mitochondrial oxidative capacity occur with statin use even in patients without statin-induced muscle complaints.

Introduction

HMG-CoA reductase inhibitors, or statins, effectively reduce blood cholesterol levels and produce a remarkable reduction in cardiovascular events.^[1] Physical activity also reduces cardiovascular risk, and the combination of statins and high level of physical fitness reduces cardiovascular mortality in patients with hyperlipidemia patients more than either treatment alone.^[2] However, 7% to 29% of patients are reported to develop muscle complaints while receiving statin treatment,^[3] and these complaints may be exacerbated by exercise.^[4–6] Although the mechanisms are poorly understood, statins have been shown to reduce muscle mitochondrial oxidative capacity and content in humans^[7–10] and impair exercise-mediated mitochondrial adaptations in skeletal muscle.^[11]

Few studies have examined the effects of statins on muscle contractile function and exercise performance, and even fewer studies have examined this in statin users with muscle complaints. For example, the Effect of Statins on Skeletal Muscle Function and Performance (STOMP) trial is, to our knowledge, the only randomized, double-blind clinical trial that has examined aerobic exercise performance and muscle strength before and after treatmentwith placebo or high-dose atorvastatin.^[12] STOMP researchers found that more patients in the atorvastatin group than in the placebo group developed muscle complaints, but there were no differences in muscle strength and endurance, aerobic performance, or physical activity levels after 6 months of treatment. Only statin-naive individualswere studied in STOMP, however, so the absence of deleterious changes in muscle function and performance may not apply to symptomatic statin users. Also, muscle biopsy specimens were not obtained in the STOMP trial to investigate whether changes in mitochondrial content and/or function occur during statin treatment andwhether they relate to muscle complaints and exercise performance.

The aim of the current study was to examine whether differences exist in aerobic exercise performance, muscle contractile function, and muscle mitochondrial oxidative capacity and content between long-term symptomatic and asymptomatic statin users, and control subjects who did not use a statin drug.

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Table 1. Participant Characteristics
Characteristics	Symptomatic Statin Users (n = 10)	Asymptomatic Statin Users (n = 10)	Control Subjects (n = 10)	P Value^a
Participants, male/female, no.	6/4	8/2	7/3	0.71
Age, median (Q25–Q75), y	61 (56–65)	65 (63–66)	61 (54–67)	0.29
Height, mean ± SD, m	1.71 ± 0.08	1.73 ± 1.07	1.77 ± 0.11	0.35
Weight, mean ± SD, kg BMI, mean ± SD, kg/m²	74.7 ± 7.1 25.6 ± 2.4	80.3 ± 10.9 26.8 ± 2.6	84.4 ± 13.1 26.7 ± 2.4	0.15 0.50
Waist circumference, mean ± SD, cm	91.2 ± 9.2	95.3 ± 9.0	94.7 ± 9.7	0.58
Hip circumference, mean ± SD, cm	99.8 ± 5.2	101.9 ± 4.0	104.0 ± 7.2	0.26
Systolic blood pressure, mean ± SD, mm Hg	134 ± 11	138 ± 13	134 ± 15	0.70
Diastolic blood pressure, mean ± SD, mm Hg	79 ± 5	82 ± 7	85 ± 7	0.12
Heart rate at rest per min, mean ± SD	65 ± 5	63 ± 10	64 ±)	0.97
PRI, median (Q₂₅–Q₇₅), AU	33.3 (23.2–60.0)	0.0 (0.0–4.1)	14 3.7 (0.0–29.2	0.03^b,c
CK, median (Q₂₅–Q₇₅), U/L	146.5 (81.8–244.0)	97.5 (55.5–158.8)	102.5 (75.3–160.0)	0.34
Total physical activity level, median	113 (74–166)	104 (75–145)	74 (50–116)	0.35
(Q₂₅–Q₇₅), METh/wk
Commuting	0 (0–0.0)	0 (0–0.5)	0 (0–20)	0.43
Activities at home or work	71 (4–122)	21 (8–76)	33 (20–73)	0.46
Leisure time activities	33 (20–56)	31 (21–83)	17 (10–22)	0.02^b,d
Sport activities	2 (0–7)	4 (0–37)	9 (0–28)	0.55
Cardiovascular medication, no.
Antiplatelet drugs	7	4	1	0.03
β-blockers	5	3	0	0.05
Angiotensin II receptor antagonists	1	1	0	1.00
Angiotensin-converting enzyme inhibitors	2	2	1	1.00
Diuretics	4	2	1	0.43
Statins	10	10	0	<0.001
Type, no.				0.61
Simvastatin	4	3	—
Atorvastatin	5	3	—
Pravastatin	1	3	—
Fluvastatin	0	1	—
Dose, mg/d, no.				0.31
10	5	1	—
20	3	4	—
40	2	5	—

Abbreviations: —, not applicable; AU, arbitrary unit; BMI, body mass index; CK, creatine kinase; METh/wk, metabolic equivalent hours per week; PRI, pain rating index; Q, quartile; SD, standard deviation.
^a P values are from ANOVA, Kruskal–Wallis one-way ANOVA, or χ² tests, and significance is set at P < 0.05. When significant differences between groups are found, pairwise comparisons were performed by Bonferroni post hoc testing.
^bPost hoc result significantly different between asymptomatic statin users and control subjects.
^cPost hoc test result significantly different between symptomatic statin users and control subjects.
^dPost hoc test result significantly different between symptomatic and asymptomatic statin users.

Table 2. Serological Markers
		Asymptomatic Statin Users (n = 10)	Control Subjects (n = 10)	P Value^a
Cholesterol, mmol/L	4.8 ± 0.7	4.9 ± 0.6	5.7 ± 0.8	0.02^b
HDL cholesterol, mmol/L LDL cholesterol, mmol/L	1.6 ± 0.5 2.7 ± 0.9	1.3 ± 0.3 3.0 ± 0.5	1.8 ± 0.4 3.5 ± 0.7	0.08 0.05^b
LDL/HDL risk index, ratio	1.9 ± 1.0	2.4 ± 0.7	2.1 ± 0.7	0.47
AST, U/L	25.9 ± 3.4	24.0 ± 5.0	23.6 ± 4.5	0.46
ALT, U/L	28.8 ± 7.0	25.8 ± 7.3	20.9 ± 4.7	0.03^b
γ-GT, median (Q₂₅–Q₇₅), U/L	20.5 (18.0–29.0)	25.5 (19.5–42.5)	26.5 (21.5–29.5)	0.47
Creatinine, μmol/L	77.8 ± 15.7	82.3 ± 14.5	83.5 ± 15.7	0.68
Vitamin D, nmol/L	67.60 ± 32.76	58.80 ± 21.13	47.80 ± 18.47	0.22

Data given as mean ± standard deviation unless otherwise indicated.
Abbreviations: AST, aspartate aminotransferase; Q, quartile; g-GT, g-glutamyl transferase.
^aP values are from ANOVA, Kruskal–Wallis one-way ANOVA, or χ² tests, and significance is set at P < 0.05. When significant differences between groups were found, pairwise comparisons were performed by Bonferroni post hoc testing.
^bPost hoc significantly different between symptomatic statin users and control subjects.

Table 3. Maximal Exercise Performance
		Asymptomatic Statin Users (n = 10)	Control Subjects (n = 10)	P Value^a
VO _2peak, mL/min	2293 ± 527	2489 ± 688	2966 ± 898	0.14
VO _2peak, median (Q₂₅–Q₇₅), mL/min/kg	29.6 (25.9–35.8)	28.1 (25.8–38.6)	34.2 (26.2–40.1)	0.87
VO _2peak, % predicted VO _2max	90.8 ± 7	90.5 ± 8	98.4 ± 8	0.10
Maximum work load, median (Q₂₅–Q₇₅), W	200 (142–237)	201 (167–262)	237 (168–325)	0.39
Maximum heart rate per min	164 ± 14	154 ± 18	169 ± 10	0.11
Maximum O₂/heart rate, mL	15.1 ± 3.2	19.1 ± 5.2	20.0 ± 7.0	0.12
VE/VCO ₂ slope	28.4 ± 2.6	29.8 ± 3.2	31.4 ± 3.8	0.15
VO ₂ at VT₁, median (Q₂₅–Q₇₅), mL/min	1249 (994–1501)	1529 (1378–2093)	1896 (1666–3199)	0.01b
VO ₂ at VT₁, % VO _2peak	54.9 ± 12.2	65.3 ± 11.0	71.4 ± 10.5	0.02^b
VO ₂ at VT₂, median (Q₂₅–Q₇₅), mL/min	1693 (1553–2282)	2050 (1657–2424)	2878 (1894–4214)	0.10
VO ₂ at VT₂, % VO _2peak	81.8 ± 8.2	80.9 ± 10.8	94.4 ± 6.3	<0.01^b,c
VO ₂ at RER = 1, median (Q₂₅–Q₇₅), mL/min	1744 (1385–2004)	2270 (1679–2873)	2645 (1585–3637)	0.14
RER end-exercise	1.2 ± 0.1	1.1 ± 0.1	1.1 ± 0.1	0.32
Lactate preexercise, mmol/L	2.1 ± 0.9	1.8 ± 0.5	1.7 ± 0.5	0.59
Lactate end-exercise, mmol/L	10.8 ± 1.8	8.1 ± 1.1	8.5 ± 2.2	0.02b,d
Preexercise Borg scale score, median (Q₂₅–Q₇₅)	6 (6–7.3)	7 (6–11)	6 (6–7)	0.30
End-exercise Borg scale score, median (Q₂₅–Q₇₅)	19 (16.5–19)	19 (17.5–19)	17 (16.5–18)	0.08

Data given as mean ±SD unless otherwise indicated.
Abbreviations: Q, quartile; RER, respiratory exchange ratio; VE, ventilation.
^a P values are from ANOVA, Kruskal–Wallis one-way ANOVA, or χ² tests, and significance is set at P < 0.05. When significant differences between groups are found, pairwise comparisons were performed by Bonferroni post hoc testing.
^bPost hoc significantly different between symptomatic statin users and control subjects.
^cPost hoc significantly different between asymptomatic statin users and control subjects.
^dPost hoc significantly different between symptomatic and asymptomatic statin users.

Table 4. Muscle Strength and Contractile Properties
		Asymptomatic Statin Users (n = 10)	Control Subjects (n = 10)	P Value^a
MVC, mean ± SD, N	522 ± 163	632 ± 112	697 ± 176	0.05^b
MVC, mean ± SD, N/kg	6.9 ± 1.1	7.9 ± 1.1	8.2 ± 1.5	0.17
Current to approximate 30% MVC, mA	101.0 (82.8–117.8)	121.5 (101.3–125.5)	121.0 (108.8–158.8)	0.03^b
Freq 50 N, mean ± SD, Hz	15.4 ± 1.4	15.7 ± 1.6	15.0 ± 1.5	0.65
Ratio 20/50, mean ± SD	0.8 ± 0.1	0.8 ± 0.1	0.8 ± 0.1	0.88
Force oscillation amplitude, %	16.5 (12.0–24.5)	20.2 (17.2–29.5)	13.1 (10.3–21.4)	0.26
Early Rt, ms	25.1 (22.6–30.0)	22.38 (20.5–24.1)	25.4 (20.8–29.9)	0.34
Half Rt, ms	35.1 (30.7–44.3)	35.3 (32.6–40.9)	46.9 (39.1–63.0)	0.04
MFR 10 Hz, %/ms	0.8 (0.8–1.0)	0.9 (0.8–1.2)	0.9 (0.7–1.1)	0.60
MFR 100 Hz, %/ms	1.3 (1.0–1.4)	1.1 (1.0–1.3)	1.1 (1.0–1.4)	0.46
Contractile speed 10 Hz ms	74.5 (73.0–79.0)	75.5 (74.8–78.5)	73.0 (55.3–79.5)	0.70
Contractile speed 100 Hz ms	25.5 (19.8–28.3)	29.5 (24.0–34.5)	35.0 (25.3–41.5)	0.06

Data presented median (Q₂₅–Q₇₅) unless otherwise indicated.
Abbreviations: SD, standard deviation; Q, quartile.
^aP values are from ANOVA, Kruskal–Wallis one-way ANOVA, or χ² tests, and significance is set at P < 0.05. When significant differences between groups are found, pairwise comparisons were performed by Bonferroni post hoc testing.
^bPost hoc significantly different between symptomatic statin users and control subjects.