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Activating Autophagy by Aerobic Exercise in Mice
Published on: February 3, 2017
Apoptosis-Inducing Factor Deficiency Induces Tissue-Specific Alterations in Autophagy: Insights from a Preclinical
Sara Laine-Menéndez1, Miguel Fernández-de la Torre1, Carmen Fiuza-Luces1
1Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigación Sanitaria Hospital '12 de Octubre' ('imas12'), 28041 Madrid, Spain.
Abstract:
We analyzed the effects of apoptosis-inducing factor (AIF) deficiency, as well as those of an exercise training intervention on autophagy across tissues (heart, skeletal muscle, cerebellum and brain), that are primarily affected by mitochondrial diseases, using a preclinical model of these conditions, the Harlequin (Hq) mouse. Autophagy markers were analyzed in: (i) 2, 3 and 6 month-old male wild-type (WT) and Hq mice, and (ii) WT and Hq male mice that were allocated to an exercise training or sedentary group. The exercise training started upon onset of the first symptoms of ataxia in Hq mice and lasted for 8 weeks. Higher content of autophagy markers and free amino acids, and lower levels of sarcomeric proteins were found in the skeletal muscle and heart of Hq mice, suggesting increased protein catabolism. Leupeptin-treatment demonstrated normal autophagic flux in the Hq heart and the absence of mitophagy. In the cerebellum and brain, a lower abundance of Beclin 1 and ATG16L was detected, whereas higher levels of the autophagy substrate p62 and LAMP1 levels were observed in the cerebellum. The exercise intervention did not counteract the autophagy alterations found in any of the analyzed tissues. In conclusion, AIF deficiency induces tissue-specific alteration of autophagy in the Hq mouse, with accumulation of autophagy markers and free amino acids in the heart and skeletal muscle, but lower levels of autophagy-related proteins in the cerebellum and brain. Exercise intervention, at least if starting when muscle atrophy and neurological symptoms are already present, is not sufficient to mitigate autophagy perturbations.
Insights
Apoptosis-inducing factor (AIF) deficiency alters autophagy in specific tissues of the Harlequin mouse model. Exercise training did not reverse these autophagy changes, even when initiated after symptom onset.
Area of Science:
- Mitochondrial Biology
- Cellular Biology
- Neuroscience
Background:
- Mitochondrial diseases often affect tissues like the heart, skeletal muscle, and brain.
- Apoptosis-inducing factor (AIF) plays a role in cellular processes, and its deficiency can impact mitochondrial function.
- Autophagy is a crucial cellular degradation process that can be dysregulated in disease states.
Purpose of the Study:
- To investigate the impact of AIF deficiency on autophagy in various tissues.
- To determine if exercise training can mitigate AIF deficiency-induced autophagy alterations.
- To analyze tissue-specific changes in autophagy markers in a preclinical model.
Main Methods:
- Utilized the Harlequin (Hq) mouse model, a preclinical model for mitochondrial diseases.
- Analyzed autophagy markers in heart, skeletal muscle, cerebellum, and brain of wild-type (WT) and Hq mice at different ages.
- Assessed the effects of an 8-week exercise training intervention initiated upon symptom onset in Hq mice.
Main Results:
- AIF deficiency led to increased autophagy markers and free amino acids, with decreased sarcomeric proteins in heart and skeletal muscle.
- Leupeptin treatment showed normal autophagic flux but no mitophagy in the Hq heart.
- Cerebellum and brain exhibited lower Beclin 1 and ATG16L, but higher p62 and LAMP1 in the cerebellum.
- Exercise intervention did not counteract the observed autophagy alterations in any tissue.
Conclusions:
- AIF deficiency causes distinct tissue-specific alterations in autophagy, characterized by accumulation in the heart and skeletal muscle, and depletion in the brain.
- Exercise intervention, when started after symptom and atrophy onset, is insufficient to ameliorate autophagy perturbations in this model.
- Findings highlight the complex role of AIF in regulating autophagy and the limited efficacy of late-stage exercise intervention.
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