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Molecular Toxicological Mechanisms of Synthetic Cathinones on C2C12 Myoblasts

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Molecular Toxicological Mechanisms of Synthetic Cathinones on C2C12 Myoblasts

Xun Zhou et al. Int J Mol Sci.

Abstract

Synthetic cathinones are popular psychoactive substances that may cause skeletal muscle damage. In addition to indirect sympathomimetic myotoxicity, these substances could be directly myotoxic. Since studies in myocytes are currently lacking, the aim of the present study was to investigate potential toxicological effects by synthetic cathinones on C2C12 myoblasts (mouse skeletal muscle cell line). We exposed C2C12 myoblasts to 3-methylmethcathinone, 4-methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone), 3,4-methylenedioxypyrovalerone (MDPV), alpha-pyrrolidinovalerophenone (α-PVP), and naphthylpyrovalerone (naphyrone) for 1 or 24 h before cell membrane integrity, ATP content, mitochondrial oxygen consumption, and mitochondrial superoxide production was measured. 3,4-Methylenedioxymethamphetamine (MDMA) was included as a reference compound. All investigated synthetic cathinones, as well as MDMA, impaired cell membrane integrity, depleted ATP levels, and increased mitochondrial superoxide concentrations in a concentration-dependent manner in the range of 50⁻2000 μM. The two pyrovalerone derivatives α-PVP and naphyrone, and MDMA, additionally impaired basal and maximal cellular respiration, suggesting mitochondrial dysfunction. Alpha-PVP inhibited complex I, naphyrone complex II, and MDMA complex I and III, whereas complex IV was not affected. We conclude that, in addition to sympathetic nervous system effects and strenuous muscle exercise, direct effects of some cathinones on skeletal muscle mitochondria may contribute to myotoxicity in susceptible synthetic cathinone drugs users.

Keywords: electron transport chain; mitochondria; skeletal muscle toxicity; synthetic cathinones.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of the synthetic cathinones included in the study and the reference substance 3,4-methylenedioxymethamphetamine (MDMA). MDPV: 3,4-methylenedioxypyrovalerone; α-PVP: alpha-pyrrolidinovalerophenone; 3-MMC: 3-methylmethcathinone
Figure 2
Figure 2
Intracellular ATP content and viable cells expressed by maintained cell membrane integrity after drug exposure for 24 h in C2C12 cells. Data are expressed as mean ± SEM of at least three independent experiments. Drug treatments were compared to vehicle control with ANOVA followed by Dunnett’s test. Significance levels for cell viability are given as * p < 0.05, ** p < 0.01, *** p < 0.001. Significance levels for ATP content are given as + p < 0.05, ++ p < 0.01, +++ p < 0.001.
Figure 3
Figure 3
Oxygen consumption rate (OCR) in C2C12 cells after 24 h drug exposure. Basal respiration, leak respiration, and maximal respiration are expressed as mean ± SEM of at least three independent experiments. Drug treatments were compared to vehicle control with ANOVA followed by Dunnett’s test. Significance levels are given as * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 4
Figure 4
Effect on the activity of the enzyme complexes of the mitochondrial electron transport chain in C2C12 cells measured using a Oxygraph-2k-high-resolution respirometer. Data are expressed as mean ± SEM of at least four independent experiments. Treatment was compared to vehicle control with an unpaired two-tailed Student’s t-test. Significance levels are given as * p < 0.05, ** p < 0.01
Figure 5
Figure 5
Mitochondrial superoxide production in C2C12 cells after 24 h drug treatment. Data are expressed as mean ± SEM of at least three independent experiments compared to vehicle control and were analyzed with ANOVA followed by Dunett’s test. Significance levels are given as * p < 0.05, ** p < 0.01, *** p < 0.001.

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