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Fitzgerald 2024 J Cachexia Sarcopenia Muscle

From Bioblast
Publications in the MiPMap
Fitzgerald LF, Lackey J, Moussa A, Shah SV, Castellanos AM, Khan S, Schonk M, Thome T, Salyers ZR, Jakkidi N, Kim K, Yang Q, Hepple RT, Ryan TE (2024) Chronic aryl hydrocarbon receptor activity impairs muscle mitochondrial function with tobacco smoking.

ยป J Cachexia Sarcopenia Muscle [Epub ahead of print]. PMID: 38333944 Open Access

Fitzgerald Liam F, Lackey Jacob, Moussa Ahmad, Shah Sohan V, Castellanos Ana Maria, Khan Shawn, Schonk Martin, Thome Trace, Salyers Zachary R, Jakkidi Nishka, Kim Kyoungrae, Yang Qinping, Hepple Russell T, Ryan Terence E (2024) J Cachexia Sarcopenia Muscle

Abstract: Accumulating evidence has demonstrated that chronic tobacco smoking directly contributes to skeletal muscle dysfunction independent of its pathological impact to the cardiorespiratory systems. The mechanisms underlying tobacco smoke toxicity in skeletal muscle are not fully resolved. In this study, the role of the aryl hydrocarbon receptor (AHR), a transcription factor known to be activated with tobacco smoke, was investigated.

AHR related gene (mRNA) expression was quantified in skeletal muscle from adult controls and patients with chronic obstructive pulmonary disease (COPD), as well as mice with and without cigarette smoke exposure. Utilizing both skeletal muscle-specific AHR knockout mice exposed to chronic repeated (5 days per week for 16 weeks) cigarette smoke and skeletal muscle-specific expression of a constitutively active mutant AHR in healthy mice, a battery of assessments interrogating muscle size, contractile function, mitochondrial energetics, and RNA sequencing were employed.

Skeletal muscle from COPD patients (N = 79, age = 67.0 ยฑ 8.4 years) had higher levels of AHR (P = 0.0451) and CYP1B1 (P < 0.0001) compared to healthy adult controls (N = 16, age = 66.5 ยฑ 6.5 years). Mice exposed to cigarette smoke displayed higher expression of Ahr (P = 0.008), Cyp1b1 (P < 0.0001), and Cyp1a1 (P < 0.0001) in skeletal muscle compared to air controls. Cigarette smoke exposure was found to impair skeletal muscle mitochondrial oxidative phosphorylation by ~50% in littermate controls (Treatment effect, P < 0.001), which was attenuated by deletion of the AHR in muscle in male (P = 0.001), but not female, mice (P = 0.37), indicating there are sex-dependent pathological effects of smoking-induced AHR activation in skeletal muscle. Viral mediated expression of a constitutively active mutant AHR in the muscle of healthy mice recapitulated the effects of cigarette smoking by decreasing muscle mitochondrial oxidative phosphorylation by ~40% (P = 0.003).

These findings provide evidence linking chronic AHR activation secondary to cigarette smoke exposure to skeletal muscle bioenergetic deficits in male, but not female, mice. AHR activation is a likely contributor to the decline in muscle oxidative capacity observed in smokers and AHR antagonism may provide a therapeutic avenue aimed to improve muscle function in COPD. โ€ข Keywords: Atrophy, Cigarette, Dioxin, Skeletal muscle โ€ข Bioblast editor: Plangger M โ€ข O2k-Network Lab: US FL Gainesville Hepple RT, US FL Gainesville Ryan TE

Labels: MiParea: Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style  Pathology: COPD 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue, Isolated mitochondria 

Regulation: PCr;Cr  Coupling state: LEAK, OXPHOS  Pathway: N, CIV, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer