The effects of statins on exercise performance

Adoption of a healthy lifestyle (e.g. physical activity) is an important
strategy for cardiovascular risk reduction. However, adopting or maintaining a
physically active lifestyle is often not feasible for statin users, as muscle
toxicity is the most frequent adverse effect of statins with rates up to 26%.
In fact, statin use has been linked to a decreased ability to perform
activities of daily living, and increased fall risk in older subjects. Some
evidence even suggests that the practice of physical exercise on top of statin
treatment can blunt the aerobic training response.

Our colleagues from the department of Pharmacology suggested a pivotal role for
mitochondrial dysfunction (complex III inhibition) in statin-induced muscle
complaints. Based on these results, we recently investigated (CMO 2015-1836) in
a cross-sectional design whether muscle of statin users with muscle complaints
has a disturbance in mitochondrial energy production capacity compared to
statin users without muscle complaints and controls. As a secondary aim, we
also looked at skeletal muscle function and whole body aerobic fitness. Our
results (explained in more detail in the introduction and rationale) clearly
indicate that muscle mitochondria are affected in statin users with muscle
complaints. However, it is currently unknown if the exercise intolerance of
statin users with muscle complaints is causally related to disturbances in
muscle mitochondrial function.

Therefore, we want to investigate whether: i) differences exist in training
response after a 12-week combined endurance- and resistance training program
between statin users with and without muscle complaints and a control group
(non-statin users) and ii) the size of the training response is depend on the
exercise-induced change in mitochondrial mass and function and substrate use in
statin users with and without muscle complaints and a control group (non-statin
users).

We hypothesize that improving both the quantity and the quality of the
mitochondria may counteract the statin-induced myocellular changes, and
optimize muscle function and overall aerobic exercise capacity. That is,
aerobic exercise specifically targets skeletal muscle mitochondria and hence
aerobic capacity and muscle fatigue. This type of training induces
mitochondrial biogenesis, which translates into an increase in both
mitochondrial content and volume and an induction of numerous enzymes related
to respiratory capacity. In addition, resistance training can profoundly
stimulate muscle cell hypertrophy by increasing net muscle protein synthesis
and is therefore ideally suited to counteract muscle wasting and strength loss.
Since exercise improves mitochondrial function and prevents muscle mass
wasting, combining aerobic and resistance exercise training may be helpful to
combat the statin-induced muscle complaints, while simultaneously improving
quality of life and exercise tolerance.

Primary Objectives:

1a. To investigate whether differences exist in training response after a
12-week combined endurance- and resistance training program between statin
users with and without muscle complaints and a control group (non-statin users).

1b. To investigate whether the size of the training response depends on the
exercise-induced change in mitochondrial mass and function and substrate use in
statin users with and without muscle complaints and a control group (non-statin
users).

Secondary Objectives:

2. To investigate whether differences exist in muscle function after a 12-week
combined endurance- and resistance training program between statin users with
and without muscle complaints and a control group (non-statin users), and
whether the change in muscle function depends on the exercise-induced change in
mitochondrial mass and function and substrate use.

3. To investigate the effect of a 12-week combined endurance- and resistance
training program on muscle pain, fatigue and quality of life in statin users
with and without muscle complaints and a control group (non-statin users).

Single-centre Intervention study

12-week combined endurance- and resistance training program

During this study, patients using statins will not be exposed to a major risk,
as standard care will not be withheld, as patients will not be taken of their
medication and will be carefully screened.

Performance of a muscle biopsy is not associated with an important health risk,
and my own experience has thought me that if subjects have received a
well-explained instruction, 100% of the participants who are found eligible for
participation, undergo a successful biopsy. Complications can include
infection, bleeding and hematoma formation (<2%), however, these complications
will resolve within 2 weeks. The biopsy procedures do not induce discomfort
and/or functional impairment and will leave a small scar only (maximal 1 cm).
The contra-indications for a muscle biopsy (e.g. use of anticoagulants) will be
carefully checked by an experienced physician during the medical screening
procedure. After the muscle biopsy, participants will receive written
instructions (Section E.4 voorlichtingsmateriaal) to which they should adhere
and pay attention to (e.g. not perform any exercise of heavy labour immediately
after the biopsy, not to take a bath or go swimming for 48h, taking a shower is
no problem.

Venous blood withdrawal can induce a local hematoma (<5%). However, this is
completely reversible within 2 weeks and will not induce permanent damage.
Taken together, the nature and extent of burden and risks associated with the
different measurements are modest.

The radiation dosage of a whole-body DEXA scan (performed without contrast
medium) is 4.2 µSv. This dosage of radiation is not associated with any health
risk.

Performance of exercise training in healthy individuals or in those with
increased cardiovascular risk is not associated with a health risk. Performance
of exercise training at levels of 90% of maximum heart rate is associated with
a transient increased risk for sudden cardiac death or myocardial infarction in
susceptible subjects. In our protocol training will not be performed at levels
of 90% of maximum heart rate or more. Furthermore, supervision during exercise
testing is ensured and will be performed according to previous guidelines
(described in the *SOP inspanningstest*) and exercise training will be
continuously and entirely supervised by a trained researcher.
In addition, we have vast experience with designing and executing training
programs in patient populations (e.g. obese subjects CMO2014-1336, patients
with heart failure CMO 2010-065). Furthermore, during the medical screening
procedure, an experienced physician will check the subject's health status
carefully and will check the eligibility of the subject to perform a maximal
aerobic exercise test (contra-indications listed in section 4.3 exclusion
criteria of this procotol) and the participation in the training program.