A study protocol to investigate if acipimox improves muscle function and sarcopenia: an open-label, uncontrolled, before-and-after experimental medicine feasibility study in community-dwelling older adults.

INTRODUCTION: Sarcopenia is the age-associated loss of muscle mass and strength. Nicotinamide adenine dinucleotide (NAD) plays a central role in both mitochondrial function and cellular ageing processes implicated in sarcopenia. NAD concentrations are low in older people with sarcopenia, and increasing skeletal muscle NAD concentrations may offer a novel therapy for this condition. Acipimox is a licensed lipid-lowering agent known to act as an NAD precursor. This open-label, uncontrolled, before-and-after proof-of-concept experimental medicine study will test whether daily supplementation with acipimox improves skeletal muscle NAD concentrations. METHODS AND ANALYSIS: Sixteen participants aged 65 and over with probable sarcopenia will receive acipimox 250 mg and aspirin 75 mg orally daily for 4 weeks, with the frequency of acipimox administration being dependent on renal function. Muscle biopsy of the vastus lateralis and MRI scanning of the lower leg will be performed at baseline before starting acipimox and after 3 weeks of treatment. Adverse events will be recorded for the duration of the trial. The primary outcome, analysed in a per-protocol population, is the change in skeletal muscle NAD concentration between baseline and follow-up. Secondary outcomes include changes in phosphocreatine recovery rate by 31P magnetic resonance spectroscopy, changes in physical performance and daily activity (handgrip strength, 4 m walk and 7-day accelerometry), changes in skeletal muscle mitochondrial respiratory function, changes in skeletal muscle mitochondrial DNA copy number and changes in NAD concentrations in whole blood as a putative biomarker for future participant selection. ETHICS AND DISSEMINATION: The trial is approved by the UK Medicines and Healthcare Products Regulatory Agency (EuDRACT 2021-000993-28) and UK Health Research Authority and Northeast - Tyne and Wear South Research Ethics Committee (IRAS 293565). Results will be made available to participants, their families, patients with sarcopenia, the public, regional and national clinical teams, and the international scientific community. PROTOCOL: Acipimox feasibility study Clinical Trial Protocol V.2 2/11/21. TRIAL REGISTRATION NUMBER: The ISRCTN trial database (ISRCTN87404878).

The role of novel motor unit magnetic resonance imaging to investigate motor unit activity in ageing skeletal muscle.

Sarcopenia is a progressive and generalized disease, more common in older adults, which manifests as a loss of muscle strength and mass. The pathophysiology of sarcopenia is still poorly understood with many mechanisms suggested. Age associated changes to the neuromuscular architecture, including motor units and their constituent muscle fibres, represent one such mechanism. Electromyography can be used to distinguish between different myopathies and produce counts of motor units. Evidence from electromyography studies suggests that with age, there is a loss of motor units, increases to the sizes of remaining units, and changes to their activity patterns. However, electromyography is invasive, can be uncomfortable, does not reveal the exact spatial position of motor units within muscle and is difficult to perform in deep muscles. We present a novel diffusion-weighted magnetic resonance imaging technique called 'motor unit magnetic resonance imaging (MUMRI)'. MUMRI aims to improve our understanding of the changes to the neuromuscular system associated with ageing, sarcopenia and other neuromuscular diseases. To date, we have demonstrated that MUMRI can be used to detect statistically significant differences in fasciculation rate of motor units between (n = 4) patients with amyotrophic lateral sclerosis (mean age ± SD: 53 ± 15) and a group of (n = 4) healthy controls (38 ± 7). Patients had significantly higher rates of fasciculation compared with healthy controls (mean = 99.1/min, range = 25.7-161.0 in patients vs. 7.7/min, range = 4.3-9.7 in controls; P < 0.05. MUMRI has detected differences in size, shape, and distribution of single human motor units between (n = 5) young healthy volunteers (29 ± 2.2) and (n = 5) healthy older volunteers (65.6 ± 14.8). The maximum size of motor unit territories in the older group was 12.4 ± 3.3 mm and 9.7 ± 2.7 mm in the young group; P < 0.05. MUMRI is an entirely non-invasive tool, which can be used to detect physiological and pathological changes to motor units in neuromuscular diseases. MUMRI also has the potential to be used as an intermediate outcome measure in sarcopenia trials.