2. Academic Validation
  3. Efavirenz, atazanavir, and ritonavir disrupt sarcoplasmic reticulum Ca2+ homeostasis in skeletal muscles

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

  • Antiviral Res. 2021 Mar:187:104975. doi: 10.1016/j.antiviral.2020.104975.
Fadhel A Alomar 1,  Chengju Tian 2,  Prasanta K Dash 2,  JoEllyn M McMillan 3,  Howard E Gendelman 2,  Santhi Gorantla 2,  Keshore R Bidasee 4
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia.
  • 2 Departments of Pharmacology and Experimental Neuroscience, USA.
  • 3 Departments of Pharmacology and Experimental Neuroscience, USA; Environment and Occupational Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
  • 4 Departments of Pharmacology and Experimental Neuroscience, USA; Environment and Occupational Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Nebraska Redox Biology Center, Lincoln, NE, USA. Electronic address: kbidasee@unmc.edu.
PMID: 33450312 DOI: 10.1016/j.antiviral.2020.104975
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.

Keywords

Atazanavir; Ca(2+) cycling; Efavirenz; HIV-1; Ritonavir; RyR1; SERCA1.; Sarcoplasmic reticulum; Skeletal muscle weakness (dynapenia).

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