Age-related loss of skeletal muscle mass and function is a major contributor to morbidity and has a profound effect on the quality of life of older people. The potential role of age-dependent mitochondrial dysfunction and cumulative oxidative stress as the underlying cause of muscle aging remains a controversial topic. Here we show that the pharmacological attenuation of age-related mitochondrial redox changes in muscle with SS31 is associated with some improvements in oxidative damage and mitophagy in muscles of old mice. However, this treatment failed to rescue the age-related muscle fiber atrophy associated with muscle atrophy and weakness. Collectively, these data imply that the muscle mitochondrial redox environment is not a key regulator of muscle fiber atrophy during sarcopenia but may play a key role in the decline of mitochondrial organelle integrity that occurs with muscle aging.

The placenta is crucial for life. It is an ephemeral but complex organ acting as the barrier interface between maternal and fetal circulations, providing exchange of gases, nutrients, hormones, waste products and immunoglobulins. Many gaps exist in our understanding of the detailed placental structure and function, particularly in relation to oxygen handling and transfer in healthy and pathological states in utero. Measurements to understand oxygen transfer in vivo in the human are limited, with no general agreement on the most appropriate methods. An invasive method for measuring partial pressure of oxygen in the intervillous space through needle electrode insertion at the time of Caesarean sections has been reported. This allows for direct measurements in vivo whilst maintaining near normal placental conditions; however, there are practical and ethical implications in using this method for determination of placental oxygenation. Furthermore, oxygen levels are likely to be highly heterogeneous within the placenta. Emerging non‐invasive techniques, such as MRI, and ex vivo research are capable of enhancing and improving current imaging methodology for placental villous structure and increase the precision of oxygen measurement within placental compartments. These techniques, in combination with mathematical modelling, have stimulated novel cross‐disciplinary approaches that could advance our understanding of placental oxygenation and its metabolism in normal and pathological pregnancies, improving clinical treatment options and ultimately outcomes for the patient. image

Aims: Lack of Cu,Zn-superoxide dismutase (CuZnSOD) in homozygous knockout mice ( Sod1 ^−/− ) leads to accelerated age-related muscle loss and weakness, but specific deletion of CuZnSOD in skeletal muscle ( mSod1KO mice) or neurons ( nSod1KO mice) resulted in only mild muscle functional deficits and failed to recapitulate the loss of mass and function observed in Sod1 ^−/− mice. To dissect any underlying cross-talk between motor neurons and skeletal muscle in the degeneration in Sod1 ^−/− mice, we characterized neuromuscular changes in the Sod1 ^−/− model compared with mSod1KO mice and examined degenerative molecular mechanisms and pathways in peripheral nerve and skeletal muscle. Results: In contrast to mSod1KO mice, myofiber atrophy in Sod1 ^−/− mice was associated with increased muscle oxidative damage, neuromuscular junction degeneration, denervation, nerve demyelination, and upregulation of proteins involved in maintenance of myelin sheaths. Proteomic analyses confirmed increased proteasomal activity and adaptive stress responses in muscle of Sod1 ^−/− mice that were absent in mSod1KO mice. Peripheral nerve from neither Sod1 ^−/− nor mSod1KO mice showed increased oxidative damage or molecular responses to increased oxidation compared with wild type mice. Differential cysteine (Cys) labeling revealed a specific redox shift in the catalytic Cys residue of peroxiredoxin 6 (Cys47) in the peripheral nerve from Sod1 ^−/− mice. Innovation and Conclusion: These findings demonstrate that neuromuscular integrity, redox mechanisms, and pathways are differentially altered in nerve and muscle of Sod1 ^−/− and mSod1KO mice. Results support the concept that impaired redox signaling, rather than oxidative damage, in peripheral nerve plays a key role in muscle loss in Sod1 ^−/− mice and potentially sarcopenia during aging. Antioxid. Redox Signal . 28, 275–295.

Age‐related skeletal muscle dysfunction is the underlying cause of morbidity that affects up to half the population aged 80 and over. Considerable evidence indicates that oxidative damage and mitochondrial dysfunction contribute to the sarcopenic phenotype that occurs with aging. To examine this, we administered the mitochondria‐targeted antioxidant mitoquinone mesylate {[10‐(4,5‐dimethoxy‐2‐methyl‐3,6‐dioxo‐1,4‐cyclohexadien‐ 1‐yl)decyl] triphenylphosphonium; 100 μM} to wild‐type C57BL/6 mice for 15 wk (from 24 to 28 mo of age) and investigated the effects on age‐related loss of muscle mass and function, changes in redox homeostasis, and mitochondrial organelle integrity and function. We found that mitoquinone mesylate treatment failed to prevent agedependent loss of skeletal muscle mass associated with myofiber atrophy or alter a variety of in situ and ex vivo muscle function analyses, including maximum isometric tetanic force, decline in force after a tetanic fatiguing protocol, and single‐fiber‐specific force. We also found evidence that long‐term mitoquinone mesylate administration did not reduce mitochondrial reactive oxygen species or induce significant changes in muscle redox homeostasis, as assessed by changes in 4‐hydroxynonenal protein adducts, protein carbonyl content, protein nitration, and DNA damage determined by the content of 8‐hydroxydeoxyguanosine. Mitochondrialmembrane potential, abundance, and respiration assessed in permeabilized myofibers were not significantly altered in response to mitoquinone mesylate treatment. Collectively, these findings demonstrate that long‐term mitochondria‐targeted mitoquinone mesylate administration failed to attenuate age‐related oxidative damage in skeletal muscle of old mice or provide any protective effect in the context of muscle aging.—Sakellariou, G. K., Pearson, T., Lightfoot, A. P., Nye, G. A., Wells, N., Giakoumaki, I. I., Griffiths, R. D., McArdle, A., Jackson, M. J. Long‐term administration of the mitochondria‐targeted antioxidant mitoquinone mesylate fails to attenuate age‐related oxidative damage or rescue the loss of muscle mass and function associated with aging of skeletal muscle. FASEB J. 30, 3771–3785 (2016) www.fasebj.org

TNF-α is a key inflammatory mediator and is proposed to induce transcriptional responses via the mitochondrial generation of Reactive Oxygen Species (ROS). The aim of this study was to determine the effect of TNF-α on the production of myokines by skeletal muscle. Significant increases were seen in the release of IL-6, MCP-1/CCL2, RANTES/CCL5 and KC/CXCL1 and this release was inhibited by treatment with Brefeldin A, suggesting a golgi-mediated release of cytokines by muscle cells. An increase was also seen in superoxide in response to treatment with TNF-α, which was localised to the mitochondria and this was also associated with activation of NF-κB. The changes in superoxide, activation of NF-kB and release of myokines were attenuated following pre-treatment with SS-31 peptide indicating that the ability of TNF-α to induce myokine release may be mediated through mitochondrial superoxide, which is, at least in part, associated with activation of the redox sensitive transcription factor NF-kB.