Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04744142 |
| Other study ID # |
S61133 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2018 |
| Est. completion date |
June 1, 2019 |
Study information
| Verified date |
February 2021 |
| Source |
KU Leuven |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Because of these anabolic properties of ketone bodies and the fact that ketone bodies prevent
muscle protein breakdown for gluconeogenesis during energetic stress, ketone bodies can be a
promising strategy to prevent or treat skeletal muscle wasting. Therefore, our aim is to
investigate the effect of 3HHB intake on muscle wasting and its adverse consequences during a
period of caloric restriction in lean females. In addition, we compare the effects of 3HHB
intake with a high protein diet, which is currently considered as the best strategy to
minimize lean loss during hypo-energetic periods. To end, we aim to investigate the
synergistic effects of the intake of 3HHB in combination with a high protein diet.
Description:
Thermodynamics state that body mass declines during periods in which energy expenditure
exceeds energy intake. This negative energy balance can be obtained either by reducing energy
intake, called caloric restriction, by increasing energy expenditure, i.e higher level of
physical activity, or the combination of both. The sustained energy deficit results in a net
loss of body weight due to losses of both fat and skeletal muscle mass in a ratio of
approximately 3:11, depending on the severity of caloric restriction, diet composition and
initial body fat percentage. Decreases in muscle mass are due to a combination of
downregulated muscle protein synthesis in conjunction with an increased
ubiquitin-proteasome-mediated muscle proteolysis, resulting in a negative net protein
turnover.
In the context of sports, many athletes try to lose body weight to achieve different goals,
such as improving performance by optimizing power-to-weight ratio, competing in a certain
body weight category or for aesthetic reasons. However, the loss of body weight is often
accompanied by detrimental loss of skeletal muscle mass, which is associated with a myriad of
negative consequences including impaired physical performance and increased susceptibility to
injury. Hence, athletes undergoing periods of caloric restriction strive for body weight loss
via fat loss, while minimizing loss of lean mass. Recent studies have demonstrated that an
increased protein intake, higher than the recommended dietary allowance (0.8g/kg/day),
attenuates the loss of muscle mass during caloric restriction. Research has shown that the
high protein diet has minor effects on muscle proteolysis compared to normal dietary protein
but restores muscle protein synthesis, which is probably the primary mechanism by which lean
mass is preserved. Specifically, in young healthy athletes, it is shown that a higher protein
intake of 1.6-2.4 g per kg body weight per day reduces the loss of muscle mass during
short-term caloric restriction periods.
In female athletes, longer periods of low energy availability (with or without an eating
disorder) are often interrelated with menstrual dysfunctions and decreased bone mineral
density, a syndrome called the 'female athlete triad'. The triad is particularly common in
sports that emphasize aesthetics or leanness and can impose lifelong health consequences.
However, interventions that minimize loss of lean mass and prevent hormonal and bone
metabolism dysregulations in females during periods of caloric restriction, are still
missing.
Ketone bodies, i.e. D-β-hydroxybutyrate (βHB), acetoacetate (AcAc) and acetone are naturally
occurring chemical compounds synthesized in the liver from circulating fatty acids under
conditions of low blood glucose and insulin levels. In normal physiological conditions, the
concentration of serum ketone levels remains low (< 0.1 mM). However, during starvation or
applying a ketogenic diet, i.e low carbohydrate content, serum concentrations of βHB and AcAc
can increase up to 5-8 mM and 1-2 mM, respectively. In these conditions, ketone bodies serve
as an alternative and more efficient energy source for various tissues, including the brain,
heart and skeletal muscle, thereby 'sparing' the glucose storages. In normal conditions, the
brain can only use glucose as an energy fuel to maintain central nervous system functions.
Therefore, sparing glucose storages during periods of energetic stress is extremely important
for survival. Besides, this sparing of glucose storages prevents the breakdown of muscle
proteins which can be used as precursors for gluconeogenesis, providing glucose for the brain
and other tissues. Hence, the availability of ketone bodies reduces the breakdown of muscle
proteins for gluconeogenesis and, thus, preserves skeletal muscle mass even when energy
availability is limited. Therefore, elevating ketone body levels may be an important strategy
to prevent skeletal muscle wasting during periods of energetic stress.
Since recently, serum levels of ketone bodies can be increased by the intake of the ketone
body ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (3HHB). This orally absorbable ketone
body ester is proven safe and well-tolerated in both animals and humans and can elevate
ketone body levels within 30 min to 5-6 mM, similar to levels after approximately one week of
fasting. The availability of this ketone body ester allows for controlled studies on the
effect of ketone bodies on muscle homeostasis without the negative side-effects of starvation
and a ketogenic diet, i.e high serum triglyceride and cholesterol levels. The effects of 3HHB
on endurance performance is still debated. However, a recent study from our lab showed that
post-exercise ingestion of 3HHB increases markers of protein synthesis, which was further
confirmed by in vitro experiments. C2C12 myoblasts showed increased leucine-mediated muscle
protein synthesis by incubation of physiological concentrations of ketone bodies. Most
recently, we found that dietary supplementation with 3HHB substantially improved survival and
maintenance of functional capacity and muscular integrity in a mouse model of cancer
cachexia.
Because of these anabolic properties of ketone bodies and the fact that ketone bodies prevent
muscle protein breakdown for gluconeogenesis during energetic stress, ketone bodies can be a
promising strategy to prevent or treat skeletal muscle wasting. Therefore, our aim is to
investigate the effect of 3HHB intake on muscle wasting and its adverse consequences during a
period of caloric restriction in lean females. In addition, we compare the effects of 3HHB
intake with a high protein diet, which is currently considered as the best strategy to
minimize lean loss during hypo-energetic periods. To end, we aim to investigate the
synergistic effects of the intake of 3HHB in combination with a high protein diet.
