The investigators will study if acute nutritional ketosis in adult GSD IIIa patients can boost muscle mitochondrial function in vivo.
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. Recently, acute NK in exercise was studied in humans. NK was found to enhance muscle mitochondrial function in athletes. The investigators will study if acute NK in adult GSD IIIa patients can boost muscle mitochondrial function in vivo.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
DOUBLE
Enrollment
6
In session II and III participants will perform an exercise test on a bicycle inside and outside the MR scanner.
University of Groningen, UMC Groningen
Groningen, Netherlands
Description of in vivo energy and proton balance during exercise in MR scanner with and without ketone ester drink: steady-state intramuscular levels of glycogen, Pi, PCr and pH and kinetic rate constant of metabolic recovery.
Time frame: 10 minutes; during in-magnet exercise test of session II and III.
time of individual desired workload
#minutes
Time frame: through completion of the maximum exercise test (of approximately 12 minutes) during study session I.
completion of supine bicycling bout at desired workload in scanner
(yes/no; if no, #minutes)
Time frame: 10 min
Muscle ultrasound density of the biceps, quadriceps, calf (gastrocnemius and/or soleus) and tibialis anterior muscles.
Will be performed during study session I by a neurologist.
Time frame: Together with the muscle force examination this assessment will take 1.5 hour.
Muscle force unilateral
Will be performed during study session I by a neurologist.
Time frame: Together with the muscle ultrasound this assessment will take 1.5 hour.
Subjective fatigue and muscle ache score
scale 0-10
Time frame: after each exercise bout and 24 hours after exercise
International Physical Activity Questionnaire
Time frame: This questionnaire will take 10 minutes to fill out. Participants will be asked to fill out the questionnaire one week before study session II and III
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Structural muscle parameters: fat infiltration.
Time frame: During the in-magnet exercise test of 10 minutes during session II and III
Change in blood glucose levels
#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.
Time frame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood ketones level (β-hydroxybutyrate, acetoacetate).
#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.
Time frame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Change of blood pH
#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.
Time frame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of free fatty acids
#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.
Time frame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of insulin
#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.
Time frame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of creatine kinase
#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.
Time frame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of ammonia
#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.
Time frame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of NT-proBNP
#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.
Time frame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of lactate
#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.
Time frame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Change of urine levels of myoglobin, ketones, tetraglucoside
Time frame: Urine will be collected through study session II and III. A study session will take place from 8 am till 2 pm.
optional: muscle metabolic profile (according to Cox et. al. 2016] of a muscle biopsy.
optional, on a patient-voluntary basis. If consent has been given a total of 4 muscle biopsies will be performed.
Time frame: This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III.
optional: individual phenotypic muscle properties (fiber type, mitochondrial density, capillary density
optional, on a patient-voluntary basis. If consent has been given a total of 4 muscle biopsies will be performed.
Time frame: This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III.
Individual physical performance during exercise; VO2 and VCO2 dynamics.
Time frame: During session I; the maximum exercise test of approximately 12 minutes and during the exercise tests of 15 minutes outside the MR scanner at session II and III.