Oral Gingival Cell Cigarette Smoke Exposure Induces Muscle Cell Metabolic Disruption

Abstract

Cigarette smoke exposure compromises health through damaging multiple physiological systems, including disrupting metabolic function. The purpose of this study was to determine the role of oral gingiva in mediating the deleterious metabolic effects of cigarette smoke exposure on skeletal muscle metabolic function. Using an in vitro conditioned medium cell model, skeletal muscle cells were incubated with medium from gingival cells treated with normal medium or medium containing suspended cigarette smoke extract (CSE). Following incubation of muscle cells with gingival cell conditioned medium, muscle cell mitochondrial respiration and insulin signaling and action were determined as an indication of overall muscle metabolic health. Skeletal muscle cells incubated with conditioned medium of CSE-treated gingival cells had a profound reduction in mitochondrial respiration and respiratory control. Furthermore, skeletal muscle cells had a greatly reduced response in insulin-stimulated Akt phosphorylation and glycogen synthesis. Altogether, these results provide a novel perspective on the mechanism whereby cigarette smoke affects systemic metabolic function. In conclusion, we found that oral gingival cells treated with CSE create an altered milieu that is sufficient to both disrupted skeletal muscle cell mitochondrial function and insulin sensitivity.

High-Mobility Group Box 1 Disrupts Metabolic Function with Cigarette Smoke Exposure in a Ceramide-Dependent Manner

“…For insulin treatments, myotubes received 100 nM insulin (Actrapid; Novo Nordisk, Plainsboro, NJ, USA) for 10 min before harvesting. Cigarette smoke extract (CSE) was generated as previously described [ 8 ], with slight modifications. Mouse bronchial alveolar macrophages were obtained following euthanasia and exsanguination as previously outlined [ 11 ].…”

“…We have previously found that smoke exposure disrupts metabolic function, including insulin sensitivity and mitochondrial physiology [ 5 , 6 ]. Certainly, multiple mechanisms likely exist that mediate the deleterious metabolic consequences, but the sphingolipid ceramide warrants particular attention given its well-established and robust role in the etiology of metabolic disruption [ 4 , 7 , 8 , 9 , 10 ], including that arising from cigarette smoke exposure [ 3 , 6 ]. Importantly, ceramide accrual with smoke exposure appears to be at least partially mediated through the activation of the receptor for advanced glycation end-products (RAGE) [ 5 , 11 ].…”

Diesel Exhaust Particle Exposure Compromises Alveolar Macrophage Mitochondrial Bioenergetics

“…Cells and tissue were prepared for mitochondrial respiration as described previously [9] before being transferred to respirometer chambers using the Oroboros O2K oxygraph (Oroboros, Innsbruck, Austria). Electron flow through complex I was supported by glutamate + malate (10 mM and 2 mM, respectively) to determine leak oxygen consumption (GML).…”

“…Unsurprisingly, consistent DEP inhalation is implicated with several cardiorespiratory disorders and mortality [7], with both epidemiological [8] and molecular [7] evidence indicating a primary role of the lung macrophage. At least some of the pathology associated with noxious stimuli exposure is a result of macrophage-induced cytokine release, which has been a focus of earlier work from our lab [4,9,10].…”

“…Interestingly, while mitochondria are an understandably prominent focus in the context of exploring metabolic health, its influence in mediating macrophage-induced metabolic disruption is lacking and the limited evidence overwhelmingly exists in non-lung tissues. We have previously found that cigarette smoke exposure alters whole body metabolic function [4,9,11], including mitochondria-specific consequences [3]. However, while cigarette smoke exposure is declining in many parts of the world, the increasing industrialization is leading to evermore exposure to diesel exhaust combustion [12].…”