Efavirenz, atazanavir, and ritonavir disrupt sarcoplasmic reticulum Ca²⁺ 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) 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.