Cigarette smoke increases cardiomyocyte ceramide accumulation and inhibits mitochondrial respiration.

BACKGROUND: Cigarette smoking is a common and lethal worldwide habit, with considerable mortality stemming from its deleterious effects on heart function. While current theories posit altered blood lipids and fibrinogen metabolism as likely mediators, none have explored the role of the sphingolipid ceramide in exacerbating heart function with smoke exposure. Ceramide production is a consequence of cigarette smoke in the lung, and considering ceramide's harmful effects on mitochondrial function, we sought to elucidate the role of ceramide in mediating smoke-induced altered heart mitochondrial respiration. METHODS: Lung cells (A549) were exposed to cigarette smoke extract (CSE) and heart cells (H9C2) were exposed to the lung-cell conditioned medium. Adult male mice were exposed sidestream cigarette smoke for 8 wk with dietary intervention and ceramide inhibition. Ceramides and heart cell or myocardial mitochondrial respiration were determined. RESULTS: Lung cell cultures revealed a robust response to cigarette smoke extract in both production and secretion of ceramides. Heart cells incubated with lung-cell conditioned medium revealed a pronounced inhibition of myocardial mitochondrial respiration, though this effect was mitigated with ceramide inhibition via myriocin. In vivo, heart ceramides increased roughly 600% in adult mice with long-term sidestream cigarette smoke exposure. This resulted in a significant ceramide-dependent reduction in left myocardial mitochondrial respiration, as heart mitochondria from the mice exposed to both smoke and myriocin injections respired normally. CONCLUSIONS: These results suggest ceramide to be an important mediator of altered myocardial mitochondrial function with cigarette smoke exposure. Thus, anti-ceramide therapies might be considered in the future to protect heart mitochondrial function with smoke exposure.

Biomechanical comparison of pectoralis major repair techniques: A systematic review and meta-regression.

Background: There are many surgical techniques when repairing pectoralis major tears. However, there is no clear consensus on which repair technique is biomechanically superior. Our purpose was to perform a systematic review and meta-regression to evaluate the most biomechanically superior pectoralis major repair technique. Methods: We performed a systematic review and meta-regression of six human cadaveric biomechanical studies evaluating fixation techniques for pectoralis major repairs. The primary outcome was the ultimate failure load. Covariates included cadaveric age, bone mineral density, implants, suture, and stitch method. Meta-regression accounted for differences in variables. Results: Compared with Krackow/Bunnell stitch method, the modified Mason-Allen stitch demonstrated a decrease in ultimate failure load by 220.6 N (95% CI, -273.0 to -168.2; p = <0.001). No differences were found between Krackow/Bunnell and whipstitch. There was an increase in ultimate failure load when utilizing suture tape by 206.6 N (95% CI, 139.5-273.7, p < 0.001). Suture anchors had a decrease in ultimate failure load by 88.1 N (95% CI, -153.4 to -22.8, p = 0.008) when compared to transosseous sutures. No differences were found between transosseous sutures and unicortical buttons. Discussion: We found the combination of suture tape in a whipstitch or Krackow/Bunnell stitch utilizing transosseous sutures or unicortical buttons is the most biomechanically superior construct for pectoralis major repairs.

Lipopolysaccharide Disrupts Mitochondrial Physiology in Skeletal Muscle via Disparate Effects on Sphingolipid Metabolism.

Lipopolysaccharides (LPS) are prevalent pathogenic molecules that are found within tissues and blood. Elevated circulating LPS is a feature of obesity and sepsis, both of which are associated with mitochondrial abnormalities that are key pathological features of LPS excess. However, the mechanism of LPS-induced mitochondrial alterations remains poorly understood. Herein we demonstrate the necessity of sphingolipid accrual in mediating altered mitochondrial physiology in skeletal muscle following LPS exposure. In particular, we found LPS elicited disparate effects on the sphingolipids dihydroceramides (DhCer) and ceramides (Cer) in both cultured myotubes and in muscle of LPS-injected mice. Although LPS-treated myotubes had reduced DhCer and increased Cer as well as increased mitochondrial respiration, muscle from LPS-injected mice manifested a reverse trend, namely elevated DhCer, but reduced Cer as well as reduced mitochondrial respiration. In addition, we found that LPS treatment caused mitochondrial fission, likely via dynamin-related protein 1, and increased oxidative stress. However, inhibition of de novo sphingolipid biosynthesis via myriocin protected normal mitochondrial function in spite of LPS, but inhibition of DhCer desaturase 1, which increases DhCer, but not Cer, exacerbated mitochondrial respiration with LPS. In an attempt to reconcile the incongruent effects of LPS in isolated muscle cells and whole muscle tissue, we incubated myotubes with conditioned medium from treated macrophages. In contrast to direct myotube LPS treatment, conditioned medium from LPS-treated macrophages reduced myotube respiration, but this was again mitigated with sphingolipid inhibition. Thus, macrophage sphingolipid production appears to be necessary for LPS-induced mitochondrial alterations in skeletal muscle tissue.