Abstract
Mitochondrial dysfunction contributes to the development of muscle disorders, including muscle wasting, muscle atrophy and degeneration. Despite the knowledge that oxidative stress closely interacts with mitochondrial dysfunction, the detailed mechanisms remain obscure. In this study, tert-butylhydroperoxide (t-BHP) was used to induce oxidative stress on differentiated C2C12 myotubes. t-BHP induced significant mitochondrial dysfunction in a time-dependent manner, accompanied by decreased myosin heavy chain (MyHC) expression at both the mRNA and protein levels. Consistently, endogenous reactive oxygen species (ROS) overproduction triggered by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), a mitochondrial oxidative phosphorylation inhibitor, was accompanied by decreased membrane potential and decreased MyHC protein content. However, the free radical scavenger N-acetyl-L-cysteine (NAC) efficiently reduced the ROS level and restored MyHC content, suggesting a close association between ROS and MyHC expression. Meanwhile, we found that both t-BHP and FCCP promoted the cleavage of optic atrophy 1 (OPA1) from the long form into short form during the early stages. In addition, the ATPase family gene 3-like 2, a mitochondrial inner membrane protease, was also markedly increased. Moreover, OPA1 knockdown in myotubes was accompanied by decreased MyHC content, whereas NAC failed to prevent FCCP-induced MyHC decrease with OPA1 knockdown, suggesting that ROS might affect MyHC content by modulating OPA1 cleavage. In addition, hydroxytyrosol acetate (HT-AC), an important compound in virgin olive oil, could significantly prevent t-BHP-induced mitochondrial membrane potential and cell viability loss in myotubes. Specifically, HT-AC inhibited t-BHP-induced OPA1 cleavage and mitochondrial morphology changes, accompanied by improvement on mitochondrial oxygen consumption capacity, ATP productive potential and activities of mitochondrial complex I, II and V. Moreover, both t-BHP- and FCCP-induced MyHC decrease was sufficiently inhibited by HT-AC. Taken together, our data provide evidence indicating that mitochondrial dysfunction-associated OPA1 cleavage may contribute to muscle degeneration, and olive oil compounds could be effective nutrients for preventing the development of muscle disorders.
Highlights
Mitochondria work as energy stations and signal transducers to preserve normal organism function, and increasing evidence shows that mitochondrial dysfunction contributes to skeletal muscle disorders.[7,8,9] Our previous study showed that strenuous exercise-induced muscle fatigue was accompanied by increased mitochondrial fission,[6] and an increase in the mitochondrial fission marker dynamin-related protein (DRP1) was found in the skeletal muscle after a high-fat diet was consumed, accompanied by mitochondrial dysfunction and triglyceride accumulation.[10]
It is known that the L-forms of Optic atrophy 1 (OPA1) undergo further processing in the matrix to produce the S-forms and that knockdown of OPA1-induced mitochondrial fragmentation is rescued by expression of the L-forms instead of the S-form of OPA1.15 In addition, the preservation of a stable pool of long form of OPA1 (L-OPA1) at the inner mitochondrial membrane is reported to be sufficient to delay mitophagy and maintain significant mitochondria content.[18]
We investigated the involvement of OPA1 cleavage and the protective effect of hydroxytyrosol acetate (HT-AC) on oxidative stress-induced mitochondrial dysfunction and muscle degeneration in C2C12 myoblast cells
Summary
Mitochondria work as energy stations and signal transducers to preserve normal organism function, and increasing evidence shows that mitochondrial dysfunction contributes to skeletal muscle disorders.[7,8,9] Our previous study showed that strenuous exercise-induced muscle fatigue was accompanied by increased mitochondrial fission,[6] and an increase in the mitochondrial fission marker dynamin-related protein (DRP1) was found in the skeletal muscle after a high-fat diet was consumed, accompanied by mitochondrial dysfunction and triglyceride accumulation.[10]. Hydroxytyrosol (HT) and hydroxytyrosol acetate (HT-AC) are well-known polyphenolic compounds found in olive oil, and HT-AC showed better antioxidant activity than HT.[28] In our previous study, we found that HT could prevent strenuous exercise-induced muscle dysfunction,[6] as well as reduce muscle lipid accumulation in mice fed a high-fat diet.[10] Since no studies have reported the effects of HTAC on muscle disorders. We investigated the involvement of OPA1 cleavage and the protective effect of HT-AC on oxidative stress-induced mitochondrial dysfunction and muscle degeneration in C2C12 myoblast cells
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