Effects of cigarette smoke on in situ mitochondrial substrate oxidation of slow- and fast-twitch skeletal muscles

Epidemiological and clinical evidence suggests that cigarette smoke exposure alters glucose and fatty acid metabolism, leading to greater susceptibility to metabolic disorders. However, the effects of cigarette smoke exposure on mitochondrial substrate oxidation in the skeletal muscle are still poorly understood. Accordingly, this study aimed to examine the acute effects of cigarette smoke on mitochondrial respiratory capacity, sensi-tivity, and concurrent utilization of palmitoylcarnitine (PC), a long-chain fatty acid, and pyruvate, a product of glycolysis, in permeabilized gastrocnemius and soleus muscle fibers exposed to an acute (1 h) dose (4 %) of cigarette smoke concentrate. Cigarette smoke decreased both mitochondrial respiratory capacity (CONTROL: 50.4 +/- 11.8 pmolO2/s/mgwt and SMOKE: 22.3 +/- 4.4 pmolO2/s/mgwt, p < 0.01) and sensitivity for pyruvate (CONTROL: 0.10 +/- 0.04 mM and SMOKE: 0.11 +/- 0.04 mM, p < 0.01) in the gastrocnemius muscle. In the soleus, only the sensitivity for pyruvate-stimulated mitochondrial respiration trended toward a decrease (CONTROL: 0.11 +/- 0.04 mM and SMOKE: 0.23 +/- 0.15 mM, p = 0.08). In contrast, cigarette smoke did not significantly alter palmitoylcarnitine-stimulated mitochondrial respiration in either muscle. In the control condition, pyruvate-supported respiration was inhibited by the concurrent addition of palmitoylcarnitine in the fast-twitch gastrocnemius muscle (-27.1 +/- 19.7 %, p < 0.05), but not in the slow-twitch soleus (-9.2 +/- 17.0 %). With cigarette smoke, the addition of palmitoylcarnitine augmented the maximal respiration rate stimulated by the concurrent addition of pyruvate in the gastrocnemius (+18.5 +/- 39.3 %, p < 0.05). However, cigarette smoke still significantly impaired mitochondrial respiratory capacity with combined substrates compared to control (p < 0.05). Our findings underscore that cigarette smoke directly impairs mitochondrial respiration of carbohydrate -derived substrates and is a primary mechanism underlying cigarette smoke-induced muscle dysfunction, which leads to a vicious cycle involving excess glucose conversion into fatty acids and lipotoxicity.

Automated summary

Epidemiological and clinical evidence shows that exposure to cigarette smoke affects glucose and fatty acid metabolism, increasing the risk of metabolic disorders. This study aimed to examine the effects of cigarette smoke on mitochondrial respiratory capacity and sensitivity in muscle fibers. The results revealed that cigarette smoke reduced mitochondrial respiratory capacity and sensitivity to pyruvate in the gastrocnemius muscle. Only the sensitivity to pyruvate-stimulated respiration showed a trend towards decrease in the soleus muscle. The findings highlight that cigarette smoke impairs mitochondrial respiration and plays a key role in smoke-induced muscle dysfunction and metabolic disturbances.