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Updated: May 13, 2026
A Preclinical Model of Sepsis-Induced Myopathy with Disuse in Mice
Published on: June 14, 2024
Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy
James K Ching1, Conrad C Weihl
1Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
Pathological phenotypes in inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (IBMPFD/ALS) include defective autophagosome and endosome maturation that result in vacuolation, weakness and muscle atrophy. The link between autophagy and IBMPFD/ALS pathobiology has been poorly understood. We examined the AKT-FOXO3 and MTOR pathways to characterize the regulation of autophagy in IBMPFD/ALS mouse muscle. We identified a defect in MTOR signaling that results in enhanced autophagosome biogenesis. Modulating MTOR signaling may therefore be a viable therapeutic target in IBMPFD/ALS.
Insights
Defects in autophagy regulation contribute to muscle weakness in inclusion body myopathy (IBM) and related disorders. Targeting the MTOR pathway may offer a therapeutic strategy for IBMPFD/ALS.
Area of Science:
- Neurodegenerative Diseases
- Muscle Biology
- Cellular Biology
Background:
- Inclusion body myopathy (IBM) with Paget disease of the bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) (IBMPFD/ALS) presents with pathological phenotypes including muscle vacuolation, weakness, and atrophy.
- These phenotypes are linked to defective autophagosome and endosome maturation, but the precise role of autophagy in IBMPFD/ALS pathobiology remains unclear.
Purpose of the Study:
- To investigate the regulation of autophagy in IBMPFD/ALS mouse muscle by examining the AKT-FOXO3 and MTOR signaling pathways.
- To elucidate the molecular mechanisms underlying autophagosome and endosome maturation defects in IBMPFD/ALS.
Main Methods:
- Utilized IBMPFD/ALS mouse models to study muscle tissue.
- Analyzed the activity and regulation of the AKT-FOXO3 and MTOR signaling pathways.
- Assessed autophagosome biogenesis and maturation processes.
Main Results:
- Identified a defect in MTOR signaling within the muscle of IBMPFD/ALS mice.
- Observed enhanced autophagosome biogenesis, suggesting a dysregulation in the autophagy pathway.
- Characterized the specific molecular alterations in MTOR signaling contributing to the disease phenotype.
Conclusions:
- MTOR signaling dysregulation is a key feature of IBMPFD/ALS pathobiology.
- Enhanced autophagosome biogenesis due to MTOR pathway defects contributes to muscle pathology.
- Modulating MTOR signaling presents a potential therapeutic avenue for treating IBMPFD/ALS.
