Research Paper Volume 14, Issue 22 pp 8900—8913

Denervation induces mitochondrial decline and exacerbates lysosome dysfunction in middle-aged mice

Matthew Triolo1,2, , Debasmita Bhattacharya1,2, , David A. Hood1,2, ,

  • 1 Muscle Health Research Centre, York University, Toronto, Ontario M3J 1P3, Canada
  • 2 School of Kinesiology and Health Science, York University, Toronto, Ontario M3J 1P3, Canada

Received: August 25, 2022       Accepted: October 24, 2022       Published: November 4, 2022
How to Cite

Copyright: © 2022 Triolo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


With age, skeletal muscle undergoes a progressive decline in size and quality. Imbalanced mitochondrial turnover and the resultant dysfunction contribute to these phenotypic alterations. Motor neuron denervation (Den) is a contributor to the etiology of muscle atrophy associated with age. Further, aged muscle exhibits reduced plasticity to both enhanced and suppressed contractile activity. It remains unclear when the onset of this blunted response occurs, and how middle-aged muscle adapts to denervation. The purpose of this study was to compare mitochondrial turnover pathways in young (Y, ~5months) and middle-aged (MA, ~15months) mice, and determine the influence of Den. Transgenic mt-Keima mice were subjected to 1,3 or 7 days of Den. Muscle mass, mitochondrial content, and PGC-1α protein were not different between Y and MA mice. However, indications of enhanced mitochondrial fission and mitophagy were evident in MA muscle which were supported by a greater abundance of lysosome proteins. Den resulted in muscle atrophy and reductions in mitochondrial protein content by 7-days. These changes occurred concomitant with modest decreases in PGC-1α protein, but without further elevations in mitophagy. Although both autophagosomal and lysosomal proteins were elevated, evidence of lysosome dysfunction was present following Den in MA mice. These data suggest that increases in fission drive an acceleration of mitophagy in muscle of MA mice to preserve mitochondrial quality. Den exacerbates the aging phenotype by reducing biogenesis in the absence of a change in mitophagy, perhaps limited by lysosomal capacity, leading to an accumulation of dysfunctional mitochondria with an age-related loss of neuromuscular innervation.


Bnip3: BCL2 Interacting Protein 3; Den: Denervation; Lamp1: Lysosome associated membrane protein 1; LC3: Microtubule-associated protein 1A/1B-light chain 3; MA: Middle-aged; OXPHOS: Oxidative phosphorylation; p62: Sequestosome 1; PGC-1α: Peroxisome proliferator gamma, coactivator 1 alpha; vATPase: Vesicular ATPase B1/2; Y: Young..