Abstract | INTRODUCTION/AIMS: Most mouse models of muscular dystrophy (MD) show mild phenotypes, which limits the translatability of experimental therapies to patients. A growing body of evidence suggests that MD is accompanied by metabolic abnormalities that could potentially exacerbate the primary muscle wasting process. Since thermoneutral (TN) housing of mice (~30°C) has been shown to affect many metabolic parameters, particularly when combined with a Western diet (WD), our aim was to determine whether the combination of TN and WD exacerbates muscle wasting in dysferlin-deficient BLAJ mice, a common model of limb-girdle MD type 2b ( LGMD2b). METHODS: The 2-mo-old wild-type (WT) and BLAJ mice were housed at TN or room temperature (RT) and fed a WD or regular chow for 9 mo. Ambulatory function, muscle histology, and protein immunoblots of skeletal muscle were assessed. RESULTS: BLAJ mice at RT and fed a chow diet showed normal ambulation function similar to WT mice, whereas 90% of BLAJ mice under WD and TN combination showed ambulatory dysfunction (p < 0.001), and an up to 4.1-fold increase in quadriceps and gastrocnemius fat infiltration. Western blotting revealed decreased autophagy marker microtubules-associated protein 1 light chain 3-B (LC3BII/LC3BI) ratio and up-regulation of protein kinase B/AKT and ribosomal protein S6 phosphorylation, suggesting inefficient cellular debris and protein clearance in TN BLAJ mice fed a WD. Male and female BLAJ mice under TN and WD combination showed heterogenous fibro-fatty infiltrate composition. DISCUSSION: TN and WD combination exacerbates rodent LGMD2b without affecting WT mice. This improves rodent modeling of human MD and helps elucidate how metabolic abnormalities may play a causal role in muscle wasting.
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Authors | Graham S Donen, Zoe White, Elodie Sauge, Morten Ritso, Marine Theret, John Boyd, Angela M Devlin, Fabio M V Rossi, Pascal Bernatchez |
Journal | Muscle & nerve
(Muscle Nerve)
Vol. 66
Issue 4
Pg. 513-522
(10 2022)
ISSN: 1097-4598 [Electronic] United States |
PMID | 35859452
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2022 Wiley Periodicals LLC. |
Chemical References |
- Dysferlin
- Ribosomal Protein S6
- Proto-Oncogene Proteins c-akt
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Topics |
- Animals
- Diet, Western
(adverse effects)
- Dysferlin
(genetics, metabolism)
- Female
- Housing
- Humans
- Male
- Mice
- Muscle, Skeletal
- Muscular Atrophy
(genetics, metabolism)
- Muscular Dystrophies
(pathology)
- Muscular Dystrophies, Limb-Girdle
(pathology)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Ribosomal Protein S6
(metabolism)
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