To investigate the potential of a novel dietary substrate preparation to enhance muscle mitochondrial function in GSD IIIa via acute nutritional ketosis. Secondary objectives are to further investigate in vivo exercise tolerance and intramuscular…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- physical performance during bicycle exercise bout 1
- VO2, VCO2 dynamics during bicycling exercise bout 1.
- steady-state in vivo intramuscular levels of glycogen, Pi, PCr, and pH during
exercise bout 2 versus rest.
- kinetic rate constants of metabolic recovery post-exercise bout 2
Secondary outcome
- time of individual desired workload upright bicycling bout (#minutes)
- completion of 10 min supine bicycling bout at desired workload in scanner
(yes/no; if no, #minutes)
- subjective fatigue and muscle ache score after each exercise bout (scale
0-10) and 24 hours after exercise
- International Physical Activity Questionnaire
- Muscle ultrasound density of the biceps, quadriceps, calf (gastrocnemius
and/or soleus) and tibialis anterior muscles.
- Muscle force unilateral (left) with a hand-held dynamometer (Type CT 3001,
C.I.T. Technics, Groningen, The Netherlands).
- Blood levels of glucose, *-hydroxybutyrate, acetoacetate, free fatty acids,
insulin, creatine kinase, ammonia, lactate, NT-proBNP and pH prior to and
post-exercise.
- Urine levels of myoglobin, ketones, tetraglucoside
- Structural muscle parameters: fat infiltration.
- optional: muscle metabolic profile (according to Cox et. al. 2016 [9]) prior
to and immediately post-exercise (on a patient-voluntary basis).
- optional: individual phenotypic muscle properties (fiber type, mitochondrial
density, capillary density prior to and immediately post-exercise (on a
patient-voluntary basis).
Background summary
Glycogen Storage Disease type IIIa (GSD IIIa) is an inborn error of
carbohydrate metabolism caused by impaired glycogen debranching enzyme (GDE)
activity. The ageing GSD IIIa cohort shows that muscle involvement -despite
dietary management- is a common disabling phenotype in adulthood. Currently, no
specific therapy has been established for muscle problems in adult GSD IIIa
patients. However, it could be hypothesized that nutritional ketosis (NK) will
be highly beneficial to patients. Amongst others, ketone bodies could take on
the role of primary energy source in exercising muscle. Collaborator Kieran
Clarke in Oxford and her team have recently produced an edible ketone ester
that can achieve acute NK in human subjects via oral ingestion without any
undesired side-effects. It was found that the ketone ester produced significant
physical performance enhancement in human athletes (Cox et al., 2016. Cell
Metabolism). The effect has been attributed to enhanced muscle mitochondrial
function in addition to glycogen sparing. Here, we will investigate if acute NK
in adult GSD IIIa patients can boost muscle mitochondrial function in vivo.
Study objective
To investigate the potential of a novel dietary substrate preparation to
enhance muscle mitochondrial function in GSD IIIa via acute nutritional
ketosis. Secondary objectives are to further investigate in vivo exercise
tolerance and intramuscular energy balance dynamics during exercise in GSD IIIa
patients and to identify phenotypic muscle properties (fiber type,
mitochondrial density, capillary density) in GSD IIIa patients before and
after exercise.
Study design
This is a randomised, blinded, comparator-controlled, 2-way cross over trial.
Intervention
oral intake of nutritional drinks; moderate-intensity exercise on bicycle
ergometer; in vivo Magnetic Resonance Spectroscopy; muscle ultrasound;
dynamometry;(optional) muscle microbiopsy; venipuncture.
Study burden and risks
For the nature and extent of the burden and risks associated with
participation, benefit and group relatedness we woulde like to refer to point
E4, E6 and E9 of this ABR form, and section 11c of the research protocol (C1.
Onderzoeksprotocol).
Hanzeplein 1
Groningen 9700RB
NL
Hanzeplein 1
Groningen 9700RB
NL
Listed location countries
Age
Inclusion criteria
-GSD III confirmed with enzyme assay and/or AGL mutation analysis and GSD IIIa further specified as deficient debranching enzyme activity in muscle or clinical and/or biochemical signs of cardiac and/or skeletal muscular involvement.
-age 18-65
Exclusion criteria
-contraindications for MRI studies (assessed by standardised questionnaire as previously used in METC 08-267/K; see UMCG section F METC documents)
-inability to perform bicycle exercise.
-intercurrent illness which may influence exercise tolerance (anemia, musculoskeletal injury, or other undiagnosed illness under investigation).
-known coronary artery disease, positive history for angina or cardiomyopathy.
-insulin-dependent diabetes mellitus.
-loss of, or an inability to give informed consent.
-pregnancy or current breastfeeding.
-any other cause which in the opinion of the investigators, may affect the participant's ability to participate in the study
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL59081.042.16 |