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 mu M), ATV (6.0 mu M), and RTV (3.0 mu M) 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 mu M), slowed the rate and amplitude of Ca2+ release from and reuptake of Ca2+ into the SR. EFV, ATV and RTV (1 nM - 20 mu M) potentiated and then displaced [H-3] ryanodine binding to rabbit skeletal muscle ryanodine receptor Ca2+ release channel (RyR1). These drugs at concentrations 0.25-31.2 mu M also increased and or decreased the open probability of RyR1 by altering its gating and conductance. ATV (<= 5 mu M) potentiated and >5 mu M inhibited the ability of sarco (endo) plasmic reticulum Ca2+-ATPase (SERCA1) to hydrolyze ATP and transport Ca2+. RTV (2.5-31.5 mu M) dose-dependently inhibited SERCA1-mediated, ATP-dependent Ca2+ transport. EFV (0.25-31.5 mu M) 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.

Automated summary

The study evaluated the potential impact of antiretroviral drugs on muscle fatigue, pain and weakness in HIV-1 infected individuals by disrupting sarcoplasmic reticulum Ca2+ cycling, suggesting that these drugs may contribute to these co-morbidities through modulation of SR Ca2+ homeostasis.