Search

Summary: We examined the effects of ∼30 days of spaceflight on glycogen synthase kinase 3 (GSK3) content and inhibitory serine phosphorylation in murine muscle and bone samples from four separate missions (BION-M1, rodent research [RR]1, RR9, and RR18). Spaceflight reduced GSK3β content across all missions, whereas its serine phosphorylation was elevated with RR18 and BION-M1. The reduction in GSK3β was linked to the reduction in type IIA fibers commonly observed with spaceflight as these fibers are particularly enriched with GSK3. We then tested the effects of inhibiting GSK3 before this fiber type shift, and we demonstrate that muscle-specific Gsk3 knockdown increased muscle mass, preserved muscle strength, and promoted the oxidative fiber type with Earth-based hindlimb unloading. In bone, GSK3 activation was enhanced after spaceflight; and strikingly, muscle-specific Gsk3 deletion increased bone mineral density in response to hindlimb unloading. Thus, future studies should test the effects of GSK3 inhibition during spaceflight.

Abstract The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) restores intracellular Ca2+ ([Ca2+]i) to resting levels after muscle contraction, ultimately eliciting relaxation. SERCA pumps are highly susceptible to tyrosine (T)‐nitration, impairing their ability to take up Ca2+ resulting in reduced muscle function and increased [Ca2+]i and cellular damage. The mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2), converts superoxide radicals into less reactive H2O2. Heterozygous deletion of SOD2 (Sod2+/−) in mice increases mitochondrial oxidative stress; however, the consequences of reduced SOD2 expression in skeletal and cardiac muscle, specifically the effect on SERCA pumps, has yet to be investigated. We obtained soleus, extensor digitorum longus (EDL), and left ventricle (LV) muscles from 6 to 7 month‐old wild‐type (WT) and Sod2+/− female C57BL/6J mice. Ca2+‐dependent SERCA activity assays were performed to assess SERCA function. Western blotting was conducted to examine the protein content of SERCA, phospholamban, and sarcolipin; and immunoprecipitation experiments were done to assess SERCA2a‐ and SERCA1a‐specific T‐nitration. Heterozygous SOD2 deletion did not alter SERCA1a or SERCA2a expression in the soleus or LV but reduced SERCA2a in the EDL compared with WT, though this was not statistically significant. Soleus muscles from Sod2+/− mice showed a significant reduction in SERCA’s apparent affinity for Ca2+ when compared to WT, corresponding with significantly elevated SERCA2a T‐nitration in the soleus. No effect was seen in the EDL or the LV. This is the first study to investigate the effects of SOD2 deficiency on muscle SERCA function and shows that it selectively impairs SERCA function in the soleus.

Abstract The sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA) is imperative for normal cardiac function regulating both muscle relaxation and contractility. SERCA2a is the predominant isoform in cardiac muscles and is inhibited by phospholamban (PLN). Under conditions of oxidative stress, SERCA2a may also be impaired by tyrosine nitration. Tafazzin (Taz) is a mitochondrial‐specific transacylase that regulates mature cardiolipin (CL) formation, and its absence leads to mitochondrial dysfunction and excessive production of reactive oxygen/nitrogen species (ROS/RNS). In the present study, we examined SERCA function, SERCA2a tyrosine nitration, and PLN expression/phosphorylation in left ventricles (LV) obtained from young (3‐5 months) and old (10‐12 months) wild‐type (WT) and Taz knockdown (TazKD) male mice. These mice are a mouse model for Barth syndrome, which is characterized by mitochondrial dysfunction, excessive ROS/RNS production, and dilated cardiomyopathy (DCM). Here, we show that maximal SERCA activity was impaired in both young and old TazKD LV, a result that correlated with elevated SERCA2a tyrosine nitration. In addition PLN protein was decreased, and its phosphorylation was increased in TazKD LV compared with control, which suggests that PLN may not contribute to the impairments in SERCA function. These changes in expression and phosphorylation of PLN may be an adaptive response aimed to improve SERCA function in TazKD mice. Nonetheless, we demonstrate for the first time that SERCA function is impaired in LVs obtained from young and old TazKD mice likely due to elevated ROS/RNS production. Future studies should determine whether improving SERCA function can improve cardiac contractility and pathology in TazKD mice.

Aristotle is more straightforward than his interpreters. A number of scholars have championed an Aristotle guided by pure inductive observation to reach a theory of the inferiority of women and slaves. This view, however, is contrary both to Aristotle’s expressed method and his stated purpose. He begins from the phainomena and his explicit goal is to defend them and the advantages of master and husband. The current power structure is founded on nature and is and must be logically and genetically superior to the arguments he makes in its favor. In general, scholars have explicated either the argument about slaves or that about women. However, each is inescapably fettered to the other. The unquestioned inferiority of slaves is the analogical basis for the hierarchy of male over female (e.g. 1252a31). The unquestioned natural inferiority of women the basis of the proof of the existence of the natural slave (54b12-16). Aristotle reveals the uncertain heart of his argument in a series of unanswered rhetorical questions (59b23-37). There are three parts to his defense. The philosophical move is to reject Plato’s unity of virtue. Mere difference in quantity (Plato’s solution) provides contingent not absolute rule. The teleological move argues from different virtues to different essences for women and slaves. Aristotle creates separate entities to be ruled. The rhetorical move is to blend analogies based on the “natural” difference between male and female with the hierarchical difference between master and slave. Thus we reach the master trope of Western philosophy: man is spirit/culture, woman is matter/nature. A series of misreadings of Aristotle’s purposes and arguments reveal how successful he has been in anchoring ideology in a politicized nature. Philosophy is not a purely intellectual exercise; it is also a call to moral action. We must ask and answer Aristotle’s rhetorical questions.