Background: Skeletal muscle atrophy involves and requires widespread changes in skeletal muscle gene expression and signaling pathway, resulting in excessive loss of muscle mass and strength, which is associated with poor prognosis and the decline of life quality in several diseases. However, the treatment of skeletal muscle atrophy remains an unresolved challenge to this day. The aim of the present study was to investigate the influence of pyrroloquinoline quinone (PQQ), a redox-active o-quinone found in various foods and mammalian tissues, on skeletal muscle atrophy, and to explore the underlying molecular mechanism. Methods: After denervation, mice were injected intraperitoneally with saline plus PQQ (5 mg/kg/d) or saline only for 14 days. The level of inflammatory cytokines in tibialis anterior (TA) muscles was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), and the level of signaling proteins of Janus kinase 2/signal transduction and activator of transcription 3 (Jak2/STAT3), TGF-β1/Smad3, JNK/p38 MAPK, and nuclear factor κB (NF-κB) signaling pathway were detected by Western blot. The skeletal muscle atrophy was evaluated by muscle wet weight ratio and cross-sectional areas (CSAs) of myofibers. The mitophagy was observed through transmission electron microscopy (TEM) analysis, and muscle fiber type transition was analyzed through fast myosin skeletal heavy chain antibody staining.
 Results: The proinflammatory cytokines IL-6, IL-1β and TNF-α were largely induced in TA muscles after sciatic nerve transection. PQQ can significantly reverse this phenomenon, as evidenced by the decreased levels of proinflammatory cytokines IL-6, IL-1β and TNF-α. Moreover, PQQ could significantly attenuate the signal activation of Jak2/STAT3, TGF-β1/Smad3, JNK/p38 MAPK, and NF-κB in skeletal muscles after sciatic nerve transection. Furthermore, PQQ alleviated skeletal muscle atrophy, mitigated mitophagy and inhibited slow-to-fast muscle fiber type transition.
 Conclusions: These results suggested that PQQ could attenuate denervation-induced skeletal muscle atrophy, mitophagy and fiber type transition through suppressing the Jak2/STAT3, TGF-β1/Smad3, JNK/p38 MAPK, and NF-κB signaling pathways.

https://atm.amegroups.com/article/viewFile/29416/pdf

PQQ ameliorates skeletal muscle atrophy, mitophagy and fiber type transition induced by denervation via inhibition of the inflammatory signaling pathways.

Mitochondrial oxidative stress induces leaky ryanodine receptor during mechanical ventilation.

The maintenance of skeletal muscle mass depends on the overall balance between the rates of protein synthesis and degradation. Thus, age-related muscle atrophy and function, commonly known as sarcopenia, may result from decreased protein synthesis, increased proteolysis, or simultaneous changes in both processes governed by complex multifactorial mechanisms. Growing evidence implicates oxidative stress and reactive oxygen species (ROS) as an essential regulator of proteolysis. Our previous studies have shown that genetic deletion of CuZn superoxide dismutase (CuZnSOD, Sod1) in mice leads to elevated oxidative stress, muscle atrophy and weakness, and an acceleration in age-related phenotypes associated with sarcopenia. The goal of this study is to determine whether oxidative stress directly influences the acceleration of proteolysis in skeletal muscle of Sod1-/- mice as a function of age. Compared to control, Sod1-/- muscle showed a significant elevation in protein carbonyls and 3-nitrotyrosine levels, suggesting high oxidative and nitrosative protein modifications were present. In addition, age-dependent muscle atrophy in Sod1-/- muscle was accompanied by an upregulation of the cysteine proteases, calpain, and caspase-3, which are known to play a key role in the initial breakdown of sarcomeres during atrophic conditions. Furthermore, an increase in oxidative stress-induced muscle atrophy was also strongly coupled with simultaneous activation of two major proteolytic systems, the ubiquitin-proteasome and lysosomal autophagy pathways. Collectively, our data suggest that chronic oxidative stress in Sod1-/- mice accelerates age-dependent muscle atrophy by enhancing coordinated activation of the proteolytic systems, thereby resulting in overall protein degradation.

Superoxide-mediated oxidative stress accelerates skeletal muscle atrophy by synchronous activation of proteolytic systems

Mechanical ventilation is an essential intervention for intensive care unit patients with acute lung injury. However, the use of controlled mechanical ventilation in both animal and human models ca...

https://journals.sagepub.com/doi/pdf/10.1177/1535370218811950

Ventilator-induced diaphragm dysfunction in critical illness.

http://www.dcyogunbakim.org/sayilar/20/buyuk/41-431.pdf

Diaphragmatic Dysfunction in Patients with ICU-Acquired Weakness and its Impact on Extubation Failure

Skeletal muscle mass is regulated by intracellular anabolic and catabolic activities. Increased catabolic activity can shift the balance towards net protein breakdown and muscle atrophy. Mitochondrial oxidative stress activates catabolism and is linked to muscle loss. Reducing mitochondrial oxidative stress is thus a plausible approach to prevent muscle atrophy. We tested this concept in age‐dependent muscle atrophy by genetically overexpressing the mitochondrial antioxidant thioredoxin‐2 (TXN2).

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/rco2.57

Overexpression of thioredoxin‐2 attenuates age‐related muscle loss by suppressing mitochondrial oxidative stress and apoptosis

Prolonged use of mechanical ventilation (MV) leads to atrophy and dysfunction of the major inspiratory muscle, the diaphragm, contributing to ventilator dependence. Numerous studies have shown that proteolysis and oxidative stress are among the major effectors of ventilator-induced diaphragm muscle dysfunction (VIDD), but the upstream initiator(s) of this process remain to be elucidated. We report here that periodic diaphragm contraction via phrenic nerve stimulation (PNS) substantially reduces MV-induced proteolytic activity and oxidative stress in the diaphragm. We show that MV rapidly induces phosphorylation of Smad3, and PNS nearly completely prevents this effect. In cultured cells, overexpressed Smad3 is sufficient to induce oxidative stress and protein degradation, whereas inhibition of Smad3 activity suppresses these events. In rats subjected to MV, inhibition of Smad3 activity by SIS3 suppresses oxidative stress and protein degradation in the diaphragm and prevents the reduction in contractility that is induced by MV. Smad3’s effect appears to link to STAT3 activity, which we previously identified as a regulator of VIDD. Inhibition of Smad3 suppresses STAT3 signaling both in vitro and in vivo. Thus, MV-induced diaphragm inactivity initiates catabolic changes via rapid activation of Smad3 signaling. An early intervention with PNS and/or pharmaceutical inhibition of Smad3 may prevent clinical VIDD.

/pdf/smad3-initiates-oxidative-stress-and-proteolysis-that-ars4v5zh68.pdf

Smad3 initiates oxidative stress and proteolysis that underlies diaphragm dysfunction during mechanical ventilation

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Overexpression of thioredoxin‐2 attenuates age‐related muscle loss by suppressing mitochondrial oxidative stress and apoptosis

Smad3 initiates oxidative stress and proteolysis that underlies diaphragm dysfunction during mechanical ventilation