Biology subjects

Thome, T.

Publications and source records attributed to Thome, T..

3 recordsLinked to original sources

bioRxiv2022

IGF-1 therapy improves muscle size and function in experimental peripheral arterial disease

CONDENSED ABSTRACTLower extremity peripheral arterial disease (PAD) has continued to increase in prevalence over the past several decades, yet therapeutic development has remained stagnant. Skeletal muscle health and function has been strongly linked to quality of life and medical outcomes in PAD patients. Using a rodent model of PAD, this study demonstrates that treatment of the ischemic limb with adeno-associated virus-mediated expression of insulin-like growth factor 1 (IGF1) significantly increases muscle size and strength, without improving limb hemodynamics. Interestingly, the effect size of IGF1 therapy was larger in female mice compared to their male counterparts, where substantial improvements in muscle specific force and a reduction in the progression of limb necrosis were observed. These findings indicate that clinical trials should carefully examine sex-dependent effects in experimental PAD therapies.

physiology↗

bioRxiv2022

Reversible thiol oxidation increases mitochondrial electron transport complex enzyme activity but not respiration in cardiomyocytes from patients with end-stage heart failure

Cardiomyocyte dysfunction in patients with end-stage heart failure with reduced ejection fraction (HFrEF) stems from mitochondrial dysfunction that contributes to an energetic crisis. Mitochondrial dysfunction reportedly relates to increased markers of oxidative stress, but the impact of reversible thiol oxidation on myocardial mitochondrial function in patients with HFrEF has not been investigated. In the present study, we assessed mitochondrial function in ventricular biopsies from patients with end-stage HFrEF in the presence and absence of the thiol reducing agent dithiothreitol (DTT). Isolated mitochondria exposed to DTT had increased enzyme activity of complexes I (p = 0.009) and III (p = 0.018) of the electron transport system, while complexes II (p = 0.630) or IV (p = 0.926) showed no changes. However, increased enzyme activity did not carry over to measurements of mitochondrial respiration in permeabilized bundles. Oxidative phosphorylation conductance (p = 0.439), maximal respiration (p = 0.312), and ADP sensitivity (p = 0.514) were unchanged by 5 mM DTT treatment. These results indicate that mitochondrial function can be modulated through reversible thiol oxidation, but other components of mitochondrial energy transfer are rate limiting in end-stage HFrEF. Optimal therapies to normalize cardiac mitochondrial respiration in patients with end-stage HFrEF may benefit from interventions to reverse thiol oxidation that limits complex I and III activities.

physiology↗

bioRxiv2021

Chronic Aryl Hydrocarbon Receptor Activity Phenocopies Smoking-induced Skeletal Muscle Impairment

BackgroundCOPD patients exhibit skeletal muscle atrophy, denervation, and reduced mitochondrial oxidative capacity. Whilst chronic tobacco smoke exposure is implicated in COPD muscle impairment, the mechanisms involved are ambiguous. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that activates detoxifying pathways with numerous exogenous ligands, including tobacco smoke. Whereas transient AHR activation is adaptive, chronic activation can be toxic. On this basis, we tested the hypothesis that chronic smoke-induced AHR activation causes adverse muscle impact. MethodsWe used clinical patient muscle samples, and in vitro (C2C12 myotubes) and in vivo models (mouse), to perform gene expression, mitochondrial function, muscle and neuromuscular junction morphology, and genetic manipulations (adeno-associated virus-mediated gene transfer). Results16 weeks tobacco smoke exposure in mice caused: muscle atrophy, neuromuscular junction degeneration, and reduced oxidative capacity. Similarly, smoke exposure reprogrammed the muscle transcriptome, with down-regulation of mitochondrial and neuromuscular junction genes. In mouse and human patient specimens, smoke exposure increased muscle AHR signaling. Mechanistically, experiments in cultured myotubes demonstrated that smoke condensate activated the AHR, caused mitochondrial impairments, and induced an AHR-dependent myotube atrophy. Finally, to isolate the role of AHR activity, expression of a constitutively active AHR mutant without smoke exposure caused atrophy and mitochondrial impairments in cultured myotubes, and muscle atrophy and neuromuscular junction degeneration in mice. ConclusionsThese results establish that chronic AHR activity, as occurs in smokers, phenocopies the atrophy, mitochondrial impairment and neuromuscular junction degeneration caused by chronic tobacco smoke exposure.

physiology↗