Available online 30 January 2024

Genetically diverse HET3 mice are susceptible to age-related neuromuscular decline

Voluntary exercise was ineffective at preventing age-related neuromuscular decline

Relative contributions of HET3 founder strain genetics moderated neuropathy onset

We assessed aging hallmarks in skin, muscle, and adipose in the genetically diverse HET3 mouse, and generated a broad dataset comparing these to individual animal diagnostic SNPs from the 4 founding inbred strains of the HET3 line. For middle- and old-aged HET3 mice, we provided running wheel exercise to ensure our observations were not purely representative of sedentary animals, but age-related phenotypes were not improved with running wheel activity. Adipose tissue fibrosis, peripheral neuropathy, and loss of neuromuscular junction integrity were consistent phenotypes in older-aged HET3 mice regardless of physical activity, but aspects of these phenotypes were moderated by the SNP% contributions of the founding strains for the HET3 line. Taken together, the genetic contribution of founder strain SNPs moderated age-related phenotypes in skin and muscle innervation and were dependent on biological sex and chronological age. However, there was not a single founder strain (BALB/cJ, C57BL/6J, C3H/HeJ, DBA/2J) that appeared to drive more protection or disease-risk across aging in this mouse line, but genetic diversity in general was more protective.

Aging

Peripheral Neuropathy

Neuromuscular

Adipose

Exercise

Founder Strain

SNP

HET3

© 2024 The Author(s). Published by Elsevier Inc.