Determining the Muscle Anabolic Properties of Phosphatidic Acid.
Condition: Sarcopenia
MeSH terms: Sarcopenia
Study type: Interventional

Summary: 
      Ageing is characterized by a loss of muscle mass that is detrimental for physical function
      and metabolic health and increases the risk of mortality. The loss of muscle protein mass
      with ageing is characterized by a blunted muscle anabolic response to nutrition and exercise.
      Thus, interventions to counteract muscle anabolic blunting in old age might assist in the
      long-term maintenance of muscle mass.

      Phosphatidic acid (hereafter defined as 'PA') is a novel nutrient compound that has been
      suggested to play an important role in muscle growth. Oral consumption of PA may amplify the
      signalling response to nutrition and exercise and restore muscle anabolic sensitivity in
      older adults. In order for PA to be 'clinically' applied as a means to mitigate muscle loss
      in aged populations, we must first understand the efficacy and mechanisms underlying the
      anabolic properties of this compound, which have yet to be defined in man. The proposed pilot
      study is needed to investigate the acute muscle metabolic properties of oral PA
      supplementation in older individuals.

      Sixteen healthy (non-obese, non-diabetic, non-smokers) older males aged 65-75 yrs will
      initially complete a lower-limb strength assessment and undergo a body composition scan.
      Between 4-14 days after these initial assessments, participants will be assigned to co-ingest
      1.5g of either phosphatidic acid (N= 8; PA) or a non-caloric placebo (N=8; PL) after
      following a bout of moderate intensity, single leg resistance exercise. A stable isotope
      infusion will be combined with serial muscle biopsies from the thigh of each leg to determine
      the measure rates of muscle protein synthesis in the fasted state and in the 'early' and
      'late' phase of feeding-only and exercise-plus-feeding.
    

Detailed description: 
      The investigators will recruit 16 healthy (non-obese, non-diabetic, non-smokers) elderly men
      aged 65-80 yrs to complete a double-blinded, parallel designed study, in which they will be
      randomly assigned to a phosphatidic acid (N= 8; PA) or placebo (N=8; PL) treatment group,
      matched closely for anthropometric characteristics. Participants will be recreationally
      active, but not involved in structured exercise training. All study procedures will be
      clearly explained and written consent obtained prior to study participation.

      Preliminary assessments Following explanation of the study and the acquisition of informed
      consent, participants will report to our laboratory at 0800 in an overnight fasted-state and
      having refrained from strenuous physical activity for >24 hrs. Participants will be weighed
      on a digital scale to the nearest 0.1 kg in light clothing. A dual x-ray absorptiometry (DXA)
      scan will be conducted to determine body composition (fat and fat-free mass). Following DXA
      scanning, single-leg one repetition maximum strength (1RM) will be determined for knee
      extension and leg press exercise machines. Selection of the limb to be exercised (dominant or
      non-dominant) will be randomized.

      Experimental trials Between 4 and 14 days after the preliminary assessments, participants
      will report to the laboratory at ∼0700 following an overnight fast, having refrained from
      strenuous physical activity for 72 hrs previously. A catheter will be inserted into a forearm
      vein of both arms for frequent blood sampling (∼80mL in total) and a continuous infusion of a
      stable isotope amino acid tracer (L- [ring] 13C6 phenylalanine). Participants will remain in
      a supine position throughout the trial with the exception of the exercise bout. After 150 min
      of steady-state tracer infusion a muscle biopsy will be obtained from the vastus lateralis
      quadriceps muscle of a randomly selected leg under local anesthesia (1% lidocaine) using the
      Bergström biopsy needle technique. Thereafter, participants will perform a bout of single-leg
      resistance exercise on the opposite leg. Exercise will consist of 6 sets of knee extension
      resistance exercise at 75% of the pre-determined 1RM; a protocol designed to elicit 8-12
      repetitions per set prior to the onset of volitional fatigue. Immediately after exercise,
      participants will ingest 750mg of PA or a placebo (both in non-identifiable capsule form)
      with water and a further 750mg of PA or placebo at 60 mins post-exercise. Thereafter,
      participants will lie in a supine position for the remainder of the trial. An individual with
      no direct study involvement will administer treatments in a double-blind manner.
      Investigators will be un-blinded to treatment arms upon completion of data analysis. At 150
      and 300 min following treatment consumption muscle biopsies will be obtained from both legs.
      Thus, a total of 5 invasive muscle biopsies will be obtained during the trial, which
      precludes the use of a crossover design in older individuals. Each biopsy will be obtained
      from a separate incision spaced ∼3cm apart. This model of study design will permit us
      determine rates of muscle protein synthesis in the postabsorptive state and over the early
      (0-2.5 h), late (2.5-5 h) and aggregate (0-5 h) time-course.

      Data Analyses To calculate muscle protein synthesis, the investigators will adopt
      sophisticated mass spectrometry techniques to determine isotopic tracer enrichment in
      biopsy-isolated muscle proteins and plasma. Intramuscular "anabolic signals" (in the
      mechanistic target of rapamycin pathway, a key regulator of cell size) will be determined via
      Western Blot (a technique to detect the content of specific phospho-proteins). Plasma insulin
      concentrations will be measured by immunoassay and plasma lipid profiles by Gas
      Chromatography Mass Spectrometry.
    

Intervention name(s): Phosphatidic Acid; Rice flour
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): To be administered a single dose of 1.5 g phosphatidic acid in capsule form (250 mg / capsule).; Rice flour placebo to be administered a single dose of 1.5 g in capsule form (250 mg / capsule).
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Parallel-designed study in which participants will be randomized to receive phosphatidic acid or placebo treatment. A parallel design was chosen due to the number of invasive muscle biopsies performed during each experimental trial.
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Nutraceuticals; Muscle anabolism; Ageing