Efavirenz, atazanavir, and ritonavir disrupt sarcoplasmic reticulum Ca 2+ homeostasis in skeletal muscles.

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) Ca ²⁺ cycling. In live-cell imaging, EFV (6.0 μM), ATV (6.0 μM), and RTV (3.0 μM) elicited Ca ²⁺ transients and blebbing of the plasma membranes of C2C12 skeletal muscle myotubes. Pretreating C2C12 skeletal muscle myotubes with the SR Ca ²⁺ release channel blocker ryanodine (50 μM), slowed the rate and amplitude of Ca ²⁺ release from and reuptake of Ca ²⁺ into the SR. EFV, ATV and RTV (1 nM - 20 μM) potentiated and then displaced [ ³ H] ryanodine binding to rabbit skeletal muscle ryanodine receptor Ca ²⁺ 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 Ca ²⁺ -ATPase (SERCA1) to hydrolyze ATP and transport Ca ²⁺ . RTV (2.5-31.5 μM) dose-dependently inhibited SERCA1-mediated, ATP-dependent Ca ²⁺ transport. EFV (0.25-31.5 μM) had no measurable effect on SERCA1's ability to hydrolyze ATP and transport Ca ²⁺ . These data support the notion that EFV, ATV and RTV could be contributing to skeletal muscle co-morbidities in PLWH by modulating SR Ca ²⁺ homeostasis.
(Copyright © 2020 Elsevier B.V. All rights reserved.)