β2-adrenergic receptor-mediated mitochondrial biogenesis improves skeletal muscle recovery following spinal cord injury

Natalie E. Scholpa, Epiphani C. Simmons, Douglas G. Tilley, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

In addition to local spinal cord dysfunction, spinal cord injury (SCI) can result in decreased skeletal muscle mitochondrial activity and muscle atrophy. Treatment with the FDA-approved β2-adrenergic receptor (ADRB2) agonist formoterol has been shown to induce mitochondrial biogenesis (MB) in both the spinal cord and skeletal muscle and, therefore, has the potential to address comprehensive mitochondrial and organ dysfunction following SCI. Female C57BL/6 mice were subjected to moderate contusion SCI (80 Kdyn) followed by daily administration of vehicle or formoterol beginning 8 h after injury, a clinically relevant time-point characterized by a 50% decrease in mtDNA content in the injury site. As measured by the Basso Mouse Scale, formoterol treatment improved locomotor recovery in SCI mice compared to vehicle treatment by 7 DPI, with continued recovery observed through 21 DPI (3.5 v. 2). SCI resulted in 15% body weight loss in all mice by 3 DPI. Mice treated with formoterol returned to pre-surgery weight by 13 DPI, while no weight gain occurred in vehicle-treated SCI mice. Remarkably, formoterol-treated mice exhibited a 30% increase in skeletal muscle mass compared to those treated with vehicle 21 DPI (0.93 v. 0.72% BW), corresponding with increased MB and decreased skeletal muscle atrophy. These effects were not observed in ADRB2 knockout mice subjected to SCI, indicating that formoterol is acting via the ADRB2 receptor. Furthermore, knockout mice exhibited decreased basal spinal cord and skeletal muscle PGC-1α expression, suggesting that ADRB2 may play a role in mitochondrial homeostasis under physiological conditions. These data provide evidence for systemic ADRB2-mediated MB as a therapeutic avenue for the treatment of SCI.

Original languageEnglish (US)
Article number113064
JournalExperimental Neurology
Volume322
DOIs
StatePublished - Dec 2019
Externally publishedYes

Keywords

  • Formoterol
  • Mitochondrial biogenesis
  • Recovery
  • Skeletal muscle
  • Spinal cord injury
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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