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Effect of chronic polypharmacy, the Drug Burden Index (DBI) and deprescribing on muscle function, fibre type and structure in aged mice: association with gut microbiome

Gizem Gemikonakli (1, 2, 3), John Mach (1, 2, 3), Trang Tran (1, 3), Susan Howlett (4), Rafael de Cabo (5), David Le Couteur (3, 6) and Sarah Hilmer (1, 2, 3)

  1. Kolling Institute, Sydney, New South Wales, Australia

  2. Royal North Shore Hosp, Sydney, New South Wales, Australia

  3. University of Sydney, Sydney, New South Wales, Australia

  4. Dalhousie University, Halifax, Canada

  5. National Institute on Aging, National Institute of Health, Maryland, USA

  6. Concord Hospital, Sydney, New South Wales, Australia

Ageing, polypharmacy (≥5 different drugs) and increasing DBI (anticholinergic/sedative medication exposure) are associated with falls and impaired physical function. Preclinical ageing models can assess underlying mechanistic changes. We investigated whether chronic therapeutic drugs (polypharmacy or monotherapy), with increasing DBI and/or ceasation (deprescribed), affected physical function and/or muscle histology in mice. 12-month-old male C57BL/6 mice commenced either control diet or study drug(s). Polypharmacy diets consisted of zero-DBI (metoprolol, simvastatin, omeprazole, paracetamol, irbesartan), low-DBI (metoprolol, simvastatin, omeprazole, paracetamol, citalopram) and high-DBI (metoprolol, simvastatin, citalopram, oxycodone, oxybutynin). Individual drugs (high-DBI regimen) were tested as monotherapy. At 21-months, animals were randomised to continue treatment or deprescribed. Rotarod performance was assessed at 12-24-months, and balance beam (6mm) at 24-months. Histological assessment of gastrocnemius muscles collected at 26-months involved H&E for fibre count, picrosirius red for collagen, and NADH fibre type staining. On the rotarod, after controlling for weight and cohort, zero-DBI mice (n=15-39) show improved motor coordination for 15-months onwards, compared to control (n=24-29; p<0.05), and at 24-months low-DBI-deprescribed (n=16) showed improved performance compared to low-DBI mice (n=19). Balance assessment showed deprescribed high-DBI (n=18) and metoprolol (n=16) mice performed better than their prescribed comparators (n=10-15; p<0.05). Preliminary analysis comparing randomly selected samples from control (n=8), high-DBI (n=4), and high-DBI-deprescribed (n=3), found no significant difference in fibre count per field, or cross-sectional area. High-DBI (n=2), control (n=4) and simvastatin (n=3) mice may have more type 2 than type 1 fibres, with no difference between groups. Muscle collagen was lower in high-DBI mice (n=6) when compared to high-DBI-deprescribed (n=6, p<0.05). Findings will be correlated to 16S faecal microbiota analyses from 12-, 15-, 21- and 24-months. Preclinical results suggest some drug regimens, and deprescribing may impact muscle function and structure. Future research will continue to characterise histological changes in all treatment groups, and 16S faecal microbiota sequencing.