Efavirenz, atazanavir, and ritonavir disrupt sarcoplasmic reticulum Ca2+ homeostasis in skeletal muscles

Fadhel A. Alomar, Chengju Tian, Prasanta K. Dash, Jo Ellyn M. McMillan, Howard E. Gendelman, Santhi Gorantla, Keshore R. Bidasee

Research output: Contribution to journalArticlepeer-review

Abstract

While muscle fatigue, pain and weakness are common co-morbidities in HIV-1 infected people, their underlying cause remain poorly defined. To this end, we evaluated whether the common antiretroviral drugs efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV) could be a contributing factor by pertubating sarcoplasmic reticulum (SR) Ca2+ cycling. In live-cell imaging, EFV (6.0 μM), ATV (6.0 μM), and RTV (3.0 μM) elicited Ca2+ transients and blebbing of the plasma membranes of C2C12 skeletal muscle myotubes. Pretreating C2C12 skeletal muscle myotubes with the SR Ca2+ release channel blocker ryanodine (50 μM), slowed the rate and amplitude of Ca2+ release from and reuptake of Ca2+ into the SR. EFV, ATV and RTV (1 nM - 20 μM) potentiated and then displaced [3H] ryanodine binding to rabbit skeletal muscle ryanodine receptor Ca2+ release channel (RyR1). These drugs at concentrations 0.25–31.2 μM also increased and or decreased the open probability of RyR1 by altering its gating and conductance. ATV (≤5 μM) potentiated and >5μM inhibited the ability of sarco (endo)plasmic reticulum Ca2+-ATPase (SERCA1) to hydrolyze ATP and transport Ca2+. RTV (2.5–31.5 μM) dose-dependently inhibited SERCA1-mediated, ATP-dependent Ca2+ transport. EFV (0.25–31.5 μM) had no measurable effect on SERCA1's ability to hydrolyze ATP and transport Ca2+. These data support the notion that EFV, ATV and RTV could be contributing to skeletal muscle co-morbidities in PLWH by modulating SR Ca2+ homeostasis.

Original languageEnglish (US)
Article number104975
JournalAntiviral Research
Volume187
DOIs
StatePublished - Mar 2021

Keywords

  • Atazanavir
  • Ca cycling
  • Efavirenz
  • HIV-1
  • Ritonavir
  • RyR1
  • SERCA1.
  • Sarcoplasmic reticulum
  • Skeletal muscle weakness (dynapenia)

ASJC Scopus subject areas

  • Pharmacology
  • Virology

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