Background Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial-targeted furazano [3,4-b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet-induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity. Methods Eighty-week-old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function. Results BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P < 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P < 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P < 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P < 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P < 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P < 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1-ubiquitin binding and LC3II, P < 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P < 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P < 0.0001) while limiting ER stress (decreased PERK signalling, P < 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase-3/9 activation, all P < 0.001), and muscle protein degradation (decreased 14-kDa actin fragment insoluble/soluble ratio, P < 0.001). Conclusions Mitochondrial uncoupling by agents such as BAM15 may mitigate age-related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.
Hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and a leading cause of cancer-related death globally. HCC is associated with an indolent clinical presentation, resulting in frequent advanced stage diagnoses where surgical resection or transplant therapies are not an option and medical therapies are largely ineffective at improving survival. As such, there is a critical need to identify and enhance primary prevention strategies to mitigate HCC-related morbidity and mortality. Obesity is an independent risk factor for the onset and progression of HCC. Furthermore, obesity is a leading cause of nonalcoholic steatohepatitis (NASH), the fasting growing etiological factor of HCC. Herein, we review evolving clinical and mechanistic associations between obesity and hepatocarcinogenesis with an emphasis on the therapeutic efficacy of prevailing lifestyle/behavioral, medical, and surgical treatment strategies for weight reduction and NASH reversal.
Concussions in the National Football League (NFL) are a rising topic of concern and debate. With the implementation of new protocols, NFL players are required to be removed from play and must follow specific processes before full return to play after sustaining a concussion. While concussion severity is the primary determinant of time-off, it is possible that other factors associated with player value influence time-off as well. The purpose of this study is to examine determinants of NFL games missed after a concussion. NFL concussion data from 2012 to 2015 were used in conjunction with player salary, position, previous concussions, average plays per game, and season during which the concussion occurred. Results indicate that quarterbacks and players who sustained multiple concussions missed more games, while players involved in more plays per game miss less games, providing evidence that player health and value are determinants of time-off after a concussion. Additionally, the number of games missed has increased each year, which could be the result of NFL efforts to increase safety and increased media attention.
Racial bias in sport is a prevalent research topic. Much of the previous research regarding bias among referees in sport focused on sports such as baseball, basketball, hockey, and soccer. Professional American football is unique because race is more clearly defined when compared to these other sports. Additionally, by examining holding penalties, which are known to be more subjective and called predominately by a single official on the field (i.e., the umpire), racial bias in officiating can be more efficiently analyzed in professional American football. The purpose of this study is to examine potential racial bias regarding holding penalties in the National Football League (NFL). Three years of data from the 2013 to 2014 through 2015 to 2016 NFL seasons were used, including the races of officials and players involved in holding penalties. Results showed no evidence of racial bias in the calling of holding penalties by White officials. However, Black umpires were found to call more holding penalties when led by a White referee. Additionally, Black players were more likely to have holding penalties called on them earlier in the game by all officials.
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