Background: Mitochondrial health is difficult to assess in vivo. Results: We have generated a reporter gene, MitoTimer, which targets mitochondria, and fluoresces green and shifts to red when oxidized, for assessment of mitochondrial content, structure, stress, and damage under physiological and pathological conditions. Conclusion: MitoTimer is useful for assessment of mitochondrial health in vivo. Significance: MitoTimer could advance mitochondrial research in multiple disciplines.

Background Exercise training enhances extracellular superoxide dismutase (EcSOD) expression in skeletal muscle and elicits positive health outcomes in individuals with diabetes. The goal of this study was to determine if enhanced skeletal muscle expression of EcSOD is sufficient to mitigate streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM). Methods and Results Exercise training promotes EcSOD expression in skeletal muscle and provides protection against DCM; however, it is not known if enhanced EcSOD expression in skeletal muscle plays a functional role in this protection. Here, we show that skeletal muscle-specific EcSOD transgenic mice (TG) are protected from cardiac hypertrophy, fibrosis and dysfunction under the condition of type-1 diabetes induced by STZ injection. We also show that both exercise training and muscle-specific transgenic expression of EcSOD result in elevated EcSOD protein in the blood and heart without increased transcription in the heart, suggesting enhanced expression of EcSOD from skeletal muscle redistributes to the heart. Importantly, cardiac tissue in TG mice displayed significantly reduced oxidative stress, aberrant cell signaling and inflammatory cytokine expression compared with wild type mice under the same diabetic condition. Conclusions Enhanced expression of EcSOD in skeletal muscle is sufficient to mitigate STZ-induced DCM through attenuation of oxidative stress, aberrant cell signaling and inflammation, suggesting a cross-organ mechanism by which exercise training improves cardiac function in diabetes.

BackgroundThe ERBB3 gene is essential for the proper development of the neural crest (NC) and its derivative populations such as Schwann cells. As with all cell fate decisions, transcriptional regulatory control plays a significant role in the progressive restriction and specification of NC derived lineages during development. However, little is known about the sequences mediating transcriptional regulation of ERBB3 or the factors that bind them.ResultsIn this study we identified three transcriptional enhancers at the ERBB3 locus and evaluated their regulatory potential in vitro in NC-derived cell types and in vivo in transgenic zebrafish. One enhancer, termed ERBB3_MCS6, which lies within the first intron of ERBB3, directs the highest reporter expression in vitro and also demonstrates epigenetic marks consistent with enhancer activity. We identify a consensus SOX10 binding site within ERBB3_MCS6 and demonstrate, in vitro, its necessity and sufficiency for the activity of this enhancer. Additionally, we demonstrate that transcription from the endogenous Erbb3 locus is dependent on Sox10. Further we demonstrate in vitro that Sox10 physically interacts with that ERBB3_MCS6. Consistent with its in vitro activity, we also show that ERBB3_MCS6 drives reporter expression in NC cells and a subset of its derivative lineages in vivo in zebrafish in a manner consistent with erbb3b expression. We also demonstrate, using morpholino analysis, that Sox10 is necessary for ERBB3_MCS6 expression in vivo in zebrafish.ConclusionsTaken collectively, our data suggest that ERBB3 may be directly regulated by SOX10, and that this control may in part be facilitated by ERBB3_MCS6.

The p38 MAPK belong to the stress‐activated kinase family, and p38γ MAPK is vital to exercise‐induced PGC‐1α expression, mitochondrial biogenesis and angiogenesis in skeletal muscle. However, the roles of p38α and p38β in skeletal muscle remain unclear likely due to redundanct function. To determine the function of these isoforms in skeletal muscle, we generated muscle‐specific p38α/β double knockout mice (DMKO). We then subjected these mice to 12 weeks of 45% high‐fat diet (HFD). DMKO mice showed improved glucose tolerance compared with wild‐type (WT) littermates on normal chow and HFD. DMKO mice showed reductions in total body weight, and muscle and epididymal fat mass compared with WT mice, accompanied by increased energy expenditure at equivalent caloric consumption. DMKO mice showed reduced exercise capacity as assessed by treadmill running. These findings demonstrate protective effects of p38α/β MAPK deletion in skeletal muscle regarding the development of insulin resistance and gains in body weight and fat mass, associated with increased energy expenditure. However, p38α/β MAPK deletion impairs exercise capacity suggesting a critical role in muscle function that requires further examination.