期刊
ANTIVIRAL RESEARCH
卷 187, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.antiviral.2020.104975
关键词
Skeletal muscle weakness (dynapenia); HIV-1; Atazanavir; Efavirenz; Ritonavir; Sarcoplasmic reticulum; Ca2+ cycling; RyR1; SERCA1
资金
- National Institutes of Health [R56 HL151602-01A1, P30 MH062261]
- UNMC's College of Medicine and Department of Pharmacology and Experimental Neuroscience
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.
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.
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