Skeletal Muscle Mitochondrial and Autophagic Dysregulation Are Modifiable in Spinal Muscular Atrophy

Area of Science:

• Mitochondrial Biology
• Neuromuscular Disorders
• Cellular Dynamics

Background:

• Spinal muscular atrophy (SMA) is a severe neuromuscular disorder with documented mitochondrial abnormalities in skeletal muscle.
• The impact of SMA progression on mitochondrial turnover and dynamics remains poorly understood.

Purpose of the Study:

• To investigate skeletal muscle mitochondrial turnover and dynamics during SMA disease progression.
• To determine the effects of therapeutic interventions on mitochondrial biology in SMA.

Main Methods:

• Analysis of severe SMA-like mice (Smn^2B/+ and Smn^2B/-) at pre-symptomatic, early, and late symptomatic stages (P9, P13, P21).
• In vivo assessment of exercise effects on skeletal muscle mitochondria.
• In vitro evaluation of urolithin A (UA) treatment on patient-derived myotubes.

Main Results:

• SMA mice showed upregulated mRNA levels of key mitochondrial transcription factors and increased markers of damaged mitochondria and autophagosome formation by P21.
• A fragmented mitochondrial phenotype and abnormal splicing of Optic atrophy 1 were observed in late-stage SMA mice.
• Exercise improved citrate synthase expression and reduced autophagosome accumulation; UA treatment enhanced autophagic flux, oxidative phosphorylation (OxPhos) proteins, and maximal oxygen consumption in patient cells.

Conclusions:

• Abnormal mitochondrial turnover and dynamics are linked to SMA progression, despite compensatory mechanisms.
• Exercise and UA demonstrate potential as therapeutic interventions targeting mitochondrial health in SMA.