Effects of Ketones on Muscle Wasting During Caloric Restriction in Lean Females
Condition: Muscle Wasting; Protein Intake; Ketosis; Caloric Restriction
MeSH terms: Muscular Atrophy; Wasting Syndrome; Cachexia
Study type: Interventional

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.
    

Detailed 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.
    

Intervention name(s): Ketone supplementation; Increased protein intake
Intervention type(s): Drug; Dietary Supplement
Intervention description(s): Subjects receive either placebo or ketone ester supplementation; Subjects receive either normal or increased protein intake
Other intervention name(s): Placebo vs ketone supplementation; Normal vs increased protein intake
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects were pair-matched for body weight, % body fat and energy intake, where after they were randomly allocated to an experimental group
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: resting metabolic rate; β-hydroxybutyrate; caloric restriction; muscle mass; ketone ester