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Evaluation of Calcium Homeostasis and Mitochondrial Function in Skeletal Muscle in Subjects With Heart Failure, Before and After Exercise Training

35 Years
65 Years
Not Enrolling
Heart Failure

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Trial Information

Evaluation of Calcium Homeostasis and Mitochondrial Function in Skeletal Muscle in Subjects With Heart Failure, Before and After Exercise Training

Heart failure (HF) is associated with a skeletal muscle dysfunction, characterized by an
increased fatigue that does not correlate with impaired myocardial function and physical
inactivity that is commonly associated with HF. We identified in skeletal muscle of HF rats,
a dysfunction of type 1 ryanodine receptors (RyR1) similar to that observed on the cardiac
channel (RyR2), due to an hyperphosphorylation of the RyR and a dissociation of the
regulatory protein FKBP12. This dysfunction, in addition to mitochondrial impairment,
contributes in this animal model to the reduced exercise capacity observed during HF. Our
goal is to analyse the impact of HF on calcium homeostasis, mitochondrial function and
oxidative stress in human skeletal muscle. This project, performed on muscle biopsies, will
also allow us to correlate calcium homeostasis and mitochondrial function (before and after
exercise training) to circulating factors (cytokines, catecholamines) susceptible to trigger
this muscle dysfunction.

This project addresses two straightforward questions about physiopathological mechanisms
involved in skeletal muscle dysfunction during HF. To this aim we have built locally a
network of laboratories and clinical services, used to work together, composed of two
services of the University Hospital of Montpellier (Dept. of Cardiology and Dept of Clinical
Physiology), an Inserm unit (U637, team 2) all interfaced by an another Inserm facility: the
Clinical Investigation Center (CIC) of Montpellier. In this project we will focus on the
dilated post-ischemic cardiomyopathy and compare two groups of patients under similar
treatments studied at different stages of HF defined by the NYHA. The first patients (class
II of NYHA) with a fraction of ejection between 40% and 30 % will be compared with patients
(class III) with an ejection fraction lower than 30% (12 males, 35-65 years old per HF). 24
voluntary healthy sedentary individuals carefully selected for similar level of activity as
for patients will be matched to the HF groups. All individuals will undergo cardiovascular
explorations (ECG and echocardiography, blood test) at the inclusion. They will perform an
exercise testing to evaluate their exercise capacity. A muscle biopsy will be performed 4
days after the exercise testing to assess the mitochondrial function and the Ca2+
homeostasis. After a rest period of 5 days, HF patients will perform a resistance-training
program (3 times per week for 10 weeks). A 2nd cardiovascular explorations, exercise testing
and muscle biopsy will then be performed to evaluate the beneficial effect of training.
Mitochondrial function will be measured by oxygraphy and ATP production. Ca2+ homeostasis
will be evaluated by confocal microscopy by recording spontaneous Ca2+ release events (i.e.
RyR activity). Mitochondrial and RyR biochemical analysis will complete these functional
studies as well as circulating factors (cytokines, catecholamine) and their associated

This project will allow us to characterize the behaviour of RyR in relation with
mitochondrial function in human skeletal muscle during HF and identify beneficial effects of
exercise training routinely proposed to HF patients. The analysis of circulating factors
will allow us to establish a relation of cause and effect between myocardial dysfunction and
muscle dysfunction. This project could thus open important perspectives in therapeutic.
Compounds analogues to JTV-519, acting in stabilizing RyR channels, could be prescribed as a
potent medication for HF. This project could thus be determinant in the comprehension of the
regulation of Ca2+ and energetic metabolism in human skeletal muscle which could be an
appropriate model to evaluate the effects of new pharmacological agents.

Inclusion Criteria:

- BMI < 30

Exclusion Criteria:

- Contra-indication to exercise testing performance and muscle biopsy

Type of Study:


Study Design:

Observational Model: Cohort, Time Perspective: Prospective

Outcome Measure:

To evaluate the skeletal muscular function (calcium homeostasis, mitochondrial function and oxidative stress) in two stages of heart failure patients compared to healthy volunteers

Outcome Time Frame:

Baseline measurement

Safety Issue:


Principal Investigator

Florence Galtier, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

CHRU de Montpellier, France


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:




Start Date:

April 2010

Completion Date:

November 2011

Related Keywords:

  • Heart Failure
  • Heart failure
  • Skeletal muscle
  • Calcium
  • Ryanodine receptor
  • Mitochondria
  • Exercise training
  • Muscle biopsy
  • Healthy volunteers
  • Heart Failure