Mitochondrial permeability transition is the downstream executioner of chronic aryl hydrocarbon receptor activation-mediated skeletal muscle atrophy
Authors: Fitzgerald Liam , Skinner Sarah , Shah Sohan , Badov Martin , Ryan Terence , Hepple Russell 
Published: May 2023

Chronic smoking is a major risk factor for a variety of diseases with established adverse skeletal muscle impact, such as chronic obstructive pulmonary disease, cardiovascular disease, and chronic kidney disease, and is also associated with an exacerbation of muscle atrophy with aging. We have previously shown that chronic activation of the aryl hydrocarbon receptor (AHR) is a pathological mechanism in skeletal muscle with chronic tobacco smoke (TS) exposure (Thome et al. J Cachex Sarcopenia Muscle 2022). In addition, we have shown that mitochondrial permeability transition (mPT), an event characterized by the formation of a non-specific pore across the mitochondrial inner membrane that results in release of reactive oxygen species and activation of Caspase 3 (Casp3; consequent to release of cytochrome c), is both necessary and sufficient for atrophy in single mouse muscle fibers cultured in vitro (Skinner et al. Cells 2021). On this basis, in this study we tested the hypothesis that mPT is the downstream mechanism by which chronic AHR activation contributes to skeletal muscle atrophy. We first cultured single mouse flexor digitorum brevis muscle fibers in a solution containing 0.02% TS condensate with and without an AHR antagonist and with and without mPT inhibition. Fiber diameter was measured at baseline and 24 h by an observer blinded to the identity of the samples. After 24 h in culture, TS-exposed muscle fibers were 14% smaller than vehicle treated muscle fibers (diameter: 25.7± 6.9 μm versus 22.2 ± 4.8 μm in vehicle vs TS exposed fibers, respectively), whereas muscle fibers co-treated with TS condensate and an AHR antagonist (26.7 ± 5.8 μm) or mPT inhibitor (25.4 ± 5.4 μm) were not different than vehicle treated muscle fibers. We then incubated small bundles of mouse tibialis anterior muscle in 0.02% TS condensate for one hour with and without an AHR antagonist to determine the impact of TS on the amount of Ca2+ needed to trigger mPT and its dependence upon the AHR. We observed that whereas acute TS exposure reduced the amount of Ca2+ needed to trigger mPT (2.14 ± 0.45 versus 0.93 ± 0.33 nmol x mg-1 muscle in vehicle vs TS, respectively), AHR antagonism prevented this effect (2.3 ± 1.2 nmol x mg-1). Therefore, consistent with our hypothesis, our results show that TS-induced muscle fiber atrophy requires mPT and this is mediated by an AHR-dependent reduction in the amount of Ca2+ necessary to trigger mPT. In view of the large number of endogenous (e.g., tryptophan metabolites and other uremic toxins) and exogenous substrates (e.g., vaping medium, environmental pollutants such as polycyclic aromatic hydrocarbons and dioxins) for the AHR, we propose that AHR-mediated sensitization of skeletal muscle mitochondria to mPT may also be relevant to muscle atrophy in other conditions besides chronic smoking.

Supported by the American Heart Association (Postdoctoral Fellowship POST836216 to L.F. Fitzgerald), James & Esther King Biomedical Research Foundation of Florida Health (operating grant 20K05 to R.T. Hepple and T.E. Ryan), and the National Institutes of Health (NIA R56 AG066758 to R.T. Hepple; NICHD T32HD043730 provided pre-doctoral support to S.K. Skinner).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.