Mitochondrial fission contributes to heat-induced oxidative stress in skeletal muscle but not hyperthermia in mice

Yu, Tianzheng; Ferdjallah, Iman; Elenberg, Falicia; Chen, Star K.; Deuster, Patricia A.; Chen, Yifan

doi:10.1016/j.lfs.2018.02.031

Cited by 28 publications

(34 citation statements)

References 29 publications

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“…The molecular mechanism as to how astaxanthin, but not quercetin, prevents heat-induced changes in mitochondrial morphology and function is not clear in the present study and remains to be further investigated. We and others have previously reported that heat exposure caused activation of mitochondrial fission protein Drp1 and cleavage of fusion protein OPA1, which shifts mitochondrial fission-fusion balance toward fission, and thereby would contribute to heat-induced mitochondrial fragmentation (Sanjuán Szklarz & Scorrano, 2012;Yu et al, 2016Yu et al, , 2018. Electron micrographs of mouse skeletal muscle showed that fragmented mitochondria in heatshocked muscle more frequently displayed lower cristae density and disorganized structure, which reflect mitochondrial dysfunction (Yu et al, 2016.…”

Section: Discussionmentioning

confidence: 94%

“…Muscle cramping and pain are among the first symptoms of heat-related illness (Becker & Stewart, 2011;Nelson, Collins, Comstock, & McKenzie, 2011), thus skeletal muscle should be considered a primary target for mitigating heat stress. In adult mouse skeletal muscle and C2C12 myoblasts, heat exposure initiates a cascade of events that can induce apoptosis (Yu, Deuster, & Chen, 2016;Yu et al, 2018). Also, heat stress stimulates the production of reactive oxygen species (ROS) that can exceed cellular antioxidant capacity, which is believed to contribute to the onset of heat-related skeletal muscle injuries (Davidson, Whyte, Bissinger, & Schiestl, 1996;Montilla et al, 2014;Yu et al, 2016Yu et al, , 2018).…”

mentioning

confidence: 99%

“…In adult mouse skeletal muscle and C2C12 myoblasts, heat exposure initiates a cascade of events that can induce apoptosis (Yu, Deuster, & Chen, 2016;Yu et al, 2018). Also, heat stress stimulates the production of reactive oxygen species (ROS) that can exceed cellular antioxidant capacity, which is believed to contribute to the onset of heat-related skeletal muscle injuries (Davidson, Whyte, Bissinger, & Schiestl, 1996;Montilla et al, 2014;Yu et al, 2016Yu et al, , 2018). The precise mechanisms of heat-related injuries, however, remain to be elucidated.…”

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confidence: 99%

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Astaxanthin but not quercetin preserves mitochondrial integrity and function, ameliorates oxidative stress, and reduces heat‐induced skeletal muscle injury

Dohl

Chen

et al. 2019

Journal Cellular Physiology

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Heat stress causes mitochondrial dysfunction and increases mitochondrial production of reactive oxygen species (ROS), both of which contribute to heat‐induced skeletal muscle injury. In this study, we tested whether either astaxanthin or quercetin, two dietary antioxidants, could ameliorate heat‐induced skeletal muscle oxidative injury. In mouse C2C12 myoblasts exposed to 43°C heat stress, astaxanthin inhibited heat‐induced ROS production in a concentration‐dependent manner (1–20 μM), whereas the ROS levels remained high in cells treated with quercetin over a range of concentrations (2–100 µM). Because mitochondria are both the main source and a primary target of heat‐induced ROS, we then tested the effects of astaxanthin and quercetin on mitochondrial integrity and function, under both normal temperature (37°C) and heat stress conditions. Quercetin treatment at 37°C induced mitochondrial fragmentation and decreased membrane potential (ΔΨ m), accompanied by reduced protein expression of the master regulator of mitochondrial biogenesis peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α). It also induced cleavage of mitochondrial inner‐membrane fusion protein OPA1. In contrast, astaxanthin at 37°C increased protein expression of PGC‐1α and mitochondrial transcription factor A (TFAM), and maintained tubular structure and normal ΔΨm. Under 43°C heat stress conditions, whereas quercetin failed to rescue C2C12 cells from injury, astaxanthin treatment prevented heat‐induced mitochondrial fragmentation and depolarization, and apoptotic cell death. We also isolated rat flexor digitorum brevis myofibers and confirmed the data from C2C12 myoblasts that astaxanthin but not quercetin preserves mitochondrial integrity and function and ameliorates heat‐induced skeletal muscle injury. These results confirm that mitochondria may be a potential therapeutic target for heat‐related illness and suggest that astaxanthin may potentially be an effective preventive strategy.

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Section: Discussionmentioning

confidence: 94%

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confidence: 99%

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confidence: 99%

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Astaxanthin but not quercetin preserves mitochondrial integrity and function, ameliorates oxidative stress, and reduces heat‐induced skeletal muscle injury

Dohl

Chen

et al. 2019

Journal Cellular Physiology

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“…This is not enough since morphological changes of mitochondria not necessarily match the changes in the levels of proteins involved in mitochondrial dynamics [97]. However, a limited number of studies such as those had used models of heart failure, chronic contractile activity, or heat exposure provided some evidence of the increased level of mitochondria fragmentation concordant with changes of fission/fusion proteins [97,98,99]. The same problem exists for mitochondria in the midpiece of the spermatozoon, which are also organized into an electrical circuit [100], possibly by means of intermitochondrial cement [101].…”

Section: Discussionmentioning

confidence: 99%

Lessons from the Discovery of Mitochondrial Fragmentation (Fission): A Review and Update

Zorov

Vorobjev

Popkov

et al. 2019

Cells

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Thirty-five years ago, we described fragmentation of the mitochondrial population in a living cell into small vesicles (mitochondrial fission). Subsequently, this phenomenon has become an object of general interest due to its involvement in the process of oxidative stress-related cell death and having high relevance to the incidence of a pathological phenotype. Tentatively, the key component of mitochondrial fission process is segregation and further asymmetric separation of a mitochondrial body yielding healthy (normally functioning) and impaired (incapable to function in a normal way) organelles with subsequent decomposition and removal of impaired elements through autophagy (mitophagy). We speculate that mitochondria contain cytoskeletal elements, which maintain the mitochondrial shape, and also are involved in the process of intramitochondrial segregation of waste products. We suggest that perturbation of the mitochondrial fission/fusion machinery and slowdown of the removal process of nonfunctional mitochondrial structures led to the increase of the proportion of impaired mitochondrial elements. When the concentration of malfunctioning mitochondria reaches a certain threshold, this can lead to various pathologies, including aging. Overall, we suggest a process of mitochondrial fission to be an essential component of a complex system controlling a healthy cell phenotype. The role of reactive oxygen species in mitochondrial fission is discussed.

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“…However, those studies have focused on mdivi-1 impairment of myotube formation during differentiation, 6,33 disruption of skeletal muscle autophagy and mitophagy, 34 or reduction of mitochondrial fragmentation following heat-induced stress. 35,36 Mitochondrial fragmentation has also been reduced in the muscle of an amyotrophic lateral sclerosis mouse model with a superoxide dismutase mutation using mdivi-1. 37 Thus, how mdivi-1 treatment alters cytoskeletal architecture and key functions of skeletal muscle, such as mitochondrial respiration and contractility, is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial division inhibitor 1 (mdivi‐1) increases oxidative capacity and contractile stress generated by engineered skeletal muscle

et al. 2020

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In skeletal muscle fibers, mitochondria are densely packed adjacent to myofibrils because adenosine triphosphate (ATP) is needed to fuel sarcomere shortening. However, despite this close physical and biochemical relationship, the effects of mitochondrial dynamics on skeletal muscle contractility are poorly understood. In this study, we analyzed the effects of Mitochondrial Division Inhibitor 1 (mdivi‐1), an inhibitor of mitochondrial fission, on the structure and function of both mitochondria and myofibrils in skeletal muscle tissues engineered on micromolded gelatin hydrogels. Treatment with mdivi‐1 did not alter myotube morphology, but did increase the mitochondrial turbidity and oxidative capacity, consistent with reduced mitochondrial fission. Mdivi‐1 also significantly increased basal, twitch, and tetanus stresses, as measured using the Muscular Thin Film (MTF) assay. Finally, mdivi‐1 increased sarcomere length, potentially due to mdivi‐1‐induced changes in mitochondrial volume and compression of myofibrils. Together, these results suggest that mdivi‐1 increases contractile stress generation, which may be caused by an increase in maximal respiration and/or sarcomere length due to increased volume of individual mitochondria. These data reinforce that mitochondria have both biochemical and biomechanical roles in skeletal muscle and that mitochondrial dynamics can be manipulated to alter muscle contractility.

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Mitochondrial fission contributes to heat-induced oxidative stress in skeletal muscle but not hyperthermia in mice

Cited by 28 publications

References 29 publications

Astaxanthin but not quercetin preserves mitochondrial integrity and function, ameliorates oxidative stress, and reduces heat‐induced skeletal muscle injury

Astaxanthin but not quercetin preserves mitochondrial integrity and function, ameliorates oxidative stress, and reduces heat‐induced skeletal muscle injury

Lessons from the Discovery of Mitochondrial Fragmentation (Fission): A Review and Update

Mitochondrial division inhibitor 1 (mdivi‐1) increases oxidative capacity and contractile stress generated by engineered skeletal muscle

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