Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05422534 |
| Other study ID # |
221073 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2023 |
| Est. completion date |
October 1, 2027 |
Study information
| Verified date |
July 2023 |
| Source |
Vanderbilt University Medical Center |
| Contact |
Delia M Woods, BSN/MSL |
| Phone |
615-322-1749 |
| Email |
delia.woods[@]vumc.org |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Frailty and sarcopenia are modifiable risk factors for morbidity and mortality in patients
with ESRD. Exercise is the recommended intervention to prevent frailty and sarcopenia,
however, many clinical trials have shown limited clinical improvement in muscle mass and
physical function. We propose that mitochondrial dysfunction is one of the deterrents to the
effectiveness of the exercise. We plan to evaluate the additive effect of HIIT and CoQ10, a
mitochondrial-targeted therapy, on mitochondrial function and physical performance.
Understanding the interplay among CoQ10, exercise, and mitochondrial function will identify
novel mechanisms to improve the efficiency of exercise. This will also serve to prevent
frailty, sarcopenia, and muscle dysfunction in patients with ESRD.
Description:
Frailty and sarcopenia in patients with end-stage renal disease (ESRD) Patients on
maintenance hemodialysis (MHD) experience frailty and sarcopenia. Approximately 73% of
patients are diagnosed with frailty at the time of initiation of dialysis. Frailty is a
multisystem impairment associated with vulnerability to stressors, and it is characterized by
the presence of three of the following criteria: unintentional weight loss, self-reported
exhaustion or fatigue, measured muscle weakness, slow walking speed, and low physical
activity. The prevalence of frailty increases with age; approximately 7% of individuals older
than 65 years of age are diagnosed as frail. Frailty is present at younger ages in patients
with ESRD on MHD than in the general population, as many as 44% of patients with ESRD younger
than 40 years are frail. Sarcopenia, defined as a reduction in muscle and/or muscle strength,
is common in patients on MHD and contributes significantly to the frailty syndrome in this
population.6 The loss of muscle power is one of the components of the frailty phenotype, and
poor muscle function is recognized as a major cause of frailty.
Muscle mass has been used as a surrogate of muscle function. While the decrease in muscle
mass usually correlates with a decrease in muscle strength,11 recent studies have shown that
the loss of muscle mass does not fully explain the decrease in muscle function. Likewise, a
study in older individuals has shown that the decline in strength is faster than the decline
in muscle mass. Furthermore, the maintenance of muscle mass does not necessarily prevent the
loss of muscle function, suggesting that the quality of the muscle may play an important role
in muscle function. Muscle abnormalities, such as fat infiltration and fibrosis, could
explain in part the discrepancy between muscle mass and function. Lack of physical activity
is a possible cause of increased intermuscular fat. A study showed that unilateral leg
suspension augmented intermuscular fat in thigh muscles. In contrast, aerobic exercise
combined with weight loss decreases intermuscular fat. A previous study showed increased
intermuscular fat in patients with ESRD compared to controls, a finding we have also observed
in our studies. Our preliminary data also showed that intermuscular fat inversely correlates
with physical function in patients with ESRD, highlighting the need to find strategies that
improve muscle quality and physical function in this population.
Exercise in ESRD Patients with ESRD have reduced muscle mass and strength compared to
controls. Resistance exercise is considered the best type of exercise to increase muscle mass
and muscle strength. Multiple studies have evaluated the effects of resistance exercise on
muscle mass and strength. In most of these studies, resistance exercise failed to elicit an
appropriate response compared to the general population. A recent study, using progressive
resistance exercise training, showed a comparable increase in muscle mass between healthy
controls and patients with ESRD, but it failed to show an improvement in physical function. A
single bout of resistance exercise increased muscle protein anabolic effects; however,
long-term effects seem to be stalled in patients with ESRD. Many other studies have evaluated
the effect of aerobic exercise on peak oxygen consumption (V̇O2peak) in patients with ESRD.
These studies showed that on average V̇O2peak increased by 17%, however, this improvement is
still less than the predicted age-adjusted V̇O2peak. These data suggest that different
exercise strategies need to be tested to examine improvements in physical function.
High-intensity interval training (HIIT) is a particular type of exercise that consists of
cycles of brief, high-intensity exercise followed by a recovery period.35 During the period
of high intensity, the target is to reach 75% or more of the peak power output. HIIT has been
largely unexplored in patients with ESRD. Only one previous pilot study showed that HIIT is
feasible and increased peak power output and physical function, but no change in muscle
mass.in patients with ESRD on MHD. The benefits of HIIT over other types of exercise regimens
(e.g. resistance exercise) reside in its ability to induce mitochondrial biogenesis and
improve mitochondrial function. However, it is still unknown if the mitochondrial changes
induced by HIIT also occur in patients with ESRD.
Mitochondrial abnormalities in skeletal muscle in patients with ESRD Mitochondria are
critical for muscle metabolism and function. We and others have previously shown that
mitochondrial abnormalities in skeletal muscle are present in patients with ESRD. These
abnormalities include a decreased activity of mitochondrial enzymes, such as citrate synthase
and hydroxy acyl-CoA dehydrogenase, and abnormal mitochondrial ultrastructure. We also found
that the mitochondrial content is reduced in patients with ESRD, probably due to increased
mitophagy and inappropriate mitochondrial biogenesis (generation of new mitochondria).
Interestingly, a recent study in a mouse model of CKD showed that reduction in skeletal
muscle mitochondrial content would precede the onset of sarcopenia. Recent studies also
suggest that mitochondrial dysfunction may play a role in the pathophysiology of sarcopenia.
Thus, therapeutic strategies aiming to preserve mitochondrial number and function could be
important in preventing the reduction of muscle mass and function in patients with ESRD.
Exercise improves mitochondrial function and induces mitochondrial biogenesis in young and
older healthy individuals. On the other hand, mitochondrial dysfunction reduces exercise
efficiency and muscle performance. Only three previous studies have evaluated the effect of
exercise on mitochondrial biology in patients with CKD. One study showed that exercise
prevented the decline in mitochondrial DNA copy number rather than increasing mitochondrial
biogenesis. Another study found a numerical but non-significant 15% increase in succinate
dehydrogenase (SDH) activity after 20 weeks of endurance training. This change in SDH
activity, as mentioned by the authors, is relatively small compared to the increase of 40% or
greater in healthy individuals after endurance exercise training. A recent study found that
aerobic exercise training increased mitochondrial enzyme activities, but this did not
correlate with changes in V̇O2peak. These data suggest that exercise-induced intrinsic
mitochondrial changes could be impaired in patients with ESRD on MHD. Changes in
mitochondrial dynamics (i.e., fusion and fission of mitochondria) also occur in response to
exercise. Mitochondrial fusion leads to enlarged mitochondria and maximizes the oxidative
capacity. Mitochondrial fission results in smaller mitochondria and is crucial for the
segregation and elimination of damaged mitochondria.68 Previous studies in humans have shown
that exercise upregulates both mitochondrial fusion and fission, however, the effects of
exercise on mitochondrial dynamics in patients with ESRD remains largely unexplored.
Coenzyme Q10 (CoQ10) as a strategy to restore mitochondrial and muscle function in ESRD The
use of mitochondrial-targeted therapies is an obvious approach to improve mitochondrial
function and consequently muscle function. CoQ10 (also called ubiquinone) improves
mitochondrial function by increasing the coupling of oxidative phosphorylation and oxygen
consumption. CoQ10 supplementation has been used in conditions associated with mitochondrial
dysfunction, in patients with hypertension, and in statin-induced myopathy. CoQ10 has also
been used to improve muscle function. Several studies have explored the effect of CoQ10
supplementation in conjunction with exercise training, showing that CoQ10 increases the
anaerobic threshold and peak oxygen consumption. Several other studies found no effect of
CoQ10 on exercise capacity, however, these studies were conducted in individuals with normal
levels of CoQ10. The effects of CoQ10 have been proven beneficial in individuals with low
plasma levels of CoQ10, such as elderly individuals on statin therapy and in patients with
heart failure. In the latter group, CoQ10 supplementation reduced mortality and improved
functional status, Also, there is an interactive effect of CoQ10 and exercise in patients
with heart failure. We and others have observed low levels of plasma CoQ10 in patients with
ESRD.24, We also observed an association between CoQ10 redox ratio and mitochondrial function
in patients with ESRD (see preliminary data). Our group found that CoQ10 supplementation
increases CoQ10 plasma levels and improves the CoQ10 redox ratio in a dose-dependent manner.
In a series of studies, our group has also shown that CoQ10 supplementation reduces isofurans
and the ratio of isofurans to F2-isoprostanes in patients with ESRD, which are potential
markers of mitochondrial dysfunction.
A recent systematic review and meta-analysis have summarized the evidence of CoQ10
supplementation in patients with CKD, not in hemodialysis, showing that CoQ10 may have a
metabolic beneficial effects, but recommending more randomized clinical trials (RCTs) to
support its use. In patients on MHD, a couple of studies have shown an antioxidant effect of
CoQ10 at similar doses that we propose to use in this study. Another study also found that
CoQ10 supplementation has a partial effect on oxidative stress in patients on MHD. In
contrast, two different studies have shown that CoQ10 does not affect exercise performance,
oxidative stress, or diastolic heart function in patients on MHD. It is important to mention
that the latter studies use a lower dose (200 mg/day) than the dose we proposed in this study
(1800 mg/day). Also, none of the previous studies have evaluated the combination of exercise
and CoQ10 supplementation. Therefore, there is a need for rigorous RCTs to define the effect
of CoQ10 in patients on MHD Recently it has been shown that knockout mice for mitofusin 2, a
protein involved in mitochondrial fusion, have low levels of mitochondrial CoQ10 and abnormal
mitochondrial respiration, a phenotype that can be reversed by CoQ10 supplementation.85
Mitofusin 2 may play a role in exporting newly synthesized CoQ10 out of the mitochondria.86,
87 Thus, abnormal mitochondrial dynamics may explain the low levels of CoQ10 in patients with
ESRD. All these data suggest that CoQ10 supplementation represents a novel strategy to
improve underlying abnormal mitochondrial function and dynamics, as well as enhance the
benefits of exercise in patients with ESRD.
Specific Aim 1: Test the hypothesis that CoQ10 enhances the beneficial effect of exercise on
mitochondrial function in patients with ESRD on MHD. We hypothesize that the combination of
home-based HIIT (HB-HIIT) and CoQ10 will have an additive effect in improving mitochondrial
function. We will assess in vivo skeletal muscle mitochondrial function measured by
31P-magnetic resonance spectroscopy (primary outcome) and physical performance measured by
the six-minute walk test (secondary outcome).
Specific Aim 2: Test the hypothesis that a combination of exercise training and CoQ10 will
improve ex-vivo mitochondrial respiration in patients with ESRD on MHD. For this Aim, muscle
biopsies will be performed in patients enrolled in our clinical trial. To evaluate intrinsic
changes in mitochondrial function, we will measure mitochondrial respiration (primary
outcome) in permeabilized fibers. We will also test the hypothesis that HIIT and CoQ10
combination has an additive effect in increasing mitochondrial content and mitochondrial
fusion in patients with ESRD (secondary outcomes). We will also evaluate the transcriptome
profiling with RNA sequencing in skeletal muscle to determine if the HIIT and CoQ10
combination upregulates muscle RNA expression of mitochondrial energy metabolism pathways.
