Open AccessImpact of Nucleoside Reverse Transcriptase Inhibitors on Mitochondrial DNA and RNA in Human Skeletal Muscle Cells
Author(s) -
Akihiko Saitoh,
Richard Haas,
Robert K. Naviaux,
Neurita G. Salva,
Justine Karoline Wong,
Stephen A. Spector
Publication year - 2008
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00434-08
Subject(s) - myogenesis , nucleoside reverse transcriptase inhibitor , myocyte , mitochondrial dna , skeletal muscle , peripheral blood mononuclear cell , reverse transcriptase , biology , reverse transcriptase inhibitor , nucleoside , didanosine , in vitro , microbiology and biotechnology , medicine , endocrinology , virology , rna , biochemistry , viral load , virus , antiretroviral therapy , gene
We previously reported that 2′,3′-dideoxyinosine (didanosine, or ddI) significantly altered mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells in human immunodeficiency virus type 1 (HIV-1)-infected children who had undetectable plasma HIV-1 RNA for more than 2 years while receiving highly active antiretroviral therapy. This research examines the in vitro effects of nucleoside reverse transcriptase inhibitors (NRTIs) on mitochondria of human skeletal muscle cells (HSMCs), including myoblasts and differentiated myotubes. mtDNA, mitochondrial RNA (mtRNA), and mRNA levels for nuclear mitochondrial regulatory factors were quantified in vitro using HSMCs, including myoblasts and differentiated myotubes, treated with NRTIs singly and in combination. After 5 days of treatment, mtDNA was significantly decreased in myoblasts and myotubes treated with ddI (P < 0.001 andP = 0.01, respectively) and ddI-containing regimens (P < 0.001 andP < 0.001, respectively) compared to levels in untreated cells. mtRNA (MTCYB ) was also significantly decreased in the myoblasts and myotubes treated with ddI (P = 0.004) and ddI-containing regimens (P < 0.001). Regardless of the NRTI regimens examined, NRTI combinations significantly decreased mtRNA (MTCO3 ) in myoblasts and myotubes (P = 0.02 andP = 0.01, respectively). No significant differences were observed for nuclear mitochondrial regulatory factor mRNA in myoblasts or myotubes when treated with NRTIs (P > 0.07). ddI and ddI-containing regimens significantly decrease mtDNA and mtRNA in HSMCs, most notably in myoblasts. These findings may be of particular importance in developing countries, where ddI is widely used for first-line treatment of HIV-infected children.