Increasing Mitochondrial Function on Skeletal Muscle Performance in Older Men

Study Overview
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Brief Summary
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As people grow older skeletal muscle gradually becomes smaller and weaker, causing reduced mobility and quality of life. To understand and reverse this negative process investigators need to find new ways of improving the ability of muscle to perform physical activity. There is some evidence that supplements may improve how the mitochondria work, and investigators want to explore this idea in more detail, by measuring how the muscles work and respond to exercise before and after taking the supplement. This will give us the basic information investigators would need to see if this is a useful idea.

Detailed Description
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A defining feature of ageing is loss of muscle mass ('sarcopenia') and associated functional weakness ('dynapenia'). A common characteristic of dynapenia is lowered mitochondrial content and metabolic function, causing reduced aerobic capacity, increased sensations of effort and impaired lipid oxidation (with resultant glucose intolerance). Exercise training improves mitochondrial and muscle function in ageing populations, however such adaptations remain below that of young counterparts, suggesting alternative approaches are required. Pre-clinical studies show that dietary supplementation with precursors of nicotinamide adenine dinucleotide (NAD+) restore mitochondrial biogenesis and oxidative capacity in ageing rodents and diabetic humans. However, whether NAD+ precursors rejuvenate mitochondrial capacity and, ultimately, muscle function in older humans is unknown. This pilot project will therefore investigate the efficacy of NAD+ precursor supplementation for increasing muscle performance in normally active older men, combined with examination of the molecular and metabolic mechanisms regulating physiological responses.

Official Title
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Assessing the Effects of Increased Mitochondrial Function on Skeletal Muscle Performance in Older Men; a Pilot Study

Conditions
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Impaired Mitochondrial Function, Muscle Performance

Intervention / Treatment
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* Dietary Supplement: Acipimox
* Dietary Supplement: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male Age between 65-75 years Body mass index between 19-29 No active cardiovascular or metabolic disease No active respiratory disease No current musculoskeletal injuries A sedentary lifestyle (i.e. does not engage in strenuous, planned physical activity) The ability to give informed consent Exclusion Criteria: Currently taking a statin drug or NSAIDs Have a current peptic ulcer Have any renal impairment Have a known hypersensitivity to Acipimox

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: active oral supplement<br>The active supplement will contain the prescription drug Acipimox (250 mgs) , a nicotinic acid precursor traditionally used to lower blood lipid levels. The supplement will be administered 3 times per day, for a 14 day period. | Dietary Supplement: Acipimox<br>* Oral supplement containing Acipimox 250mgs as the active ingredient in blinded label tablet form.<br>|
| Placebo Comparator: placebo supplement<br>The placebo supplement will contain only cellulose microcrystalline. This is an inert substance widely used in many pill and tablet formulations. It is an insoluble fibre and is not absorbed into the blood stream therefore is unlikely to cause toxicity when taken orally. | Dietary Supplement: placebo<br>* The placebo supplement will contain only cellulose microcrystalline. This is an inert substance widely used in many pill and tablet formulations. It is an insoluble fibre and is not absorbed into the blood stream therefore is unlikely to cause toxicity when taken orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mitochondrial function | Mitochondria will be extracted from muscle samples immediately post-biopsy (biopsies taken baseline, day 7 and day 14) and analysed for content and subsequently for oxidative respiratory function using the Seahorse technique, and maximal rates of Adenosine Triphosphate (ATP) production. | Baseline, day 7, day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chronic changes in habitual muscle protein synthetic rates | baseline saliva samples then daily saliva samples following oral ingestion of the stable isotope deuterium oxide (D2O, or 'heavy water') will be analysed by gas-chromatography-pyrolysis-isotope ratio mass-spectrometry analysis. | Baseline and then daily for 14 days |