High concentration of sodium fluoride in drinking water induce hypertrophy versus atrophy in mouse skeletal muscle via modulation of sarcomeric proteins

J Hazard Mater. 2022 Jun 15;432:128654. doi: 10.1016/j.jhazmat.2022.128654. Epub 2022 Mar 9.


Fluoride at high doses is a well-known toxic agent for the musculoskeletal system, primarily in bone and cartilage cells. Research on fluoride toxicity concerning particularly on the skeletal muscle is scanty. We hypothesized that during skeletal fluorosis, along with bone, muscle is also affected, so we have evaluated the effects of Sodium fluoride (NaF) on mouse skeletal muscles. Sodium fluoride (80 ppm) was administered to 5-week-old C57BL6 mice drinking water for 15 and 60 days, respectively. We carried out histology, primary culture, molecular and proteomic analysis of fluoride administered mouse skeletal muscles. Results indicated an increase in the muscle mass (hypertrophy) in vivo and myotubes ex vivo by activating the IGF1/PI3/Akt/mTOR signalling pathway due to short term NaF exposure. The long-term exposure of mice to NaF caused loss of muscle proteins leading to muscle atrophy due to activation of the ubiquitin-proteasome pathway. Differentially expressed proteins were characterized and mapped using a proteomic approach. Moreover, the factors responsible for protein synthesis and PI3/Akt/mTOR pathway were upregulated, leading to muscle hypertrophy during the short term NaF exposure. Long term exposure to NaF resulted in down-regulation of metabolic pathways. Elevated myostatin resulted in the up-regulation of the muscle-specific E3 ligases-MuRF1, promoting the ubiquitination and proteasome-mediated degradation of critical sarcomeric proteins.

Keywords: PI3/Akt/mTOR pathway; Skeletal muscle atrophy; Skeletal muscle hypertrophy; Sodium fluoride; Ubiquitin-proteasome pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drinking Water*
  • Fluorides / toxicity
  • Hypertrophy / chemically induced
  • Hypertrophy / metabolism
  • Hypertrophy / pathology
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism
  • Muscular Atrophy / chemically induced
  • Muscular Atrophy / metabolism
  • Muscular Atrophy / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Proteomics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sodium Fluoride* / metabolism
  • Sodium Fluoride* / toxicity
  • TOR Serine-Threonine Kinases / metabolism


  • Drinking Water
  • Sodium Fluoride
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Proteasome Endopeptidase Complex
  • Fluorides