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