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Exercise-Induced Hepatic Mitochondrial Reprogramming Across Muscle-Gut-Thyroid Axes in MASLD/MASH
Jonas M McCaffrey1, Jamal A Ibdah2,3,4,5
1School of Medicine, University of Missouri, Columbia, MO 65212, USA.
International Journal of Molecular Sciences
|July 28, 2026
Summary
Exercise therapy for metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) involves mitochondrial reprogramming. This process enhances hepatic mitochondrial function, improving metabolic flexibility and reducing liver disease progression.
Area of Science:
- Hepatology and Metabolic Disorders
- Mitochondrial Biology
- Exercise Physiology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are increasing global health concerns.
- These conditions stem from complex interactions involving hepatic lipid accumulation, insulin resistance, inflammation, and mitochondrial dysfunction.
- Exercise is a key lifestyle therapy, offering benefits beyond weight loss through coordinated molecular adaptations.
Purpose of the Study:
- To introduce hepatic mitochondrial reprogramming as a framework for understanding exercise's benefits in MASLD/MASH.
- To elucidate the molecular mechanisms by which exercise improves hepatic mitochondrial function and metabolic health.
- To explore how exercise-induced adaptations may complement pharmacologic treatments.
Main Methods:
- Review of existing literature on exercise, MASLD/MASH, and mitochondrial biology.
- Analysis of molecular signaling pathways activated by exercise, including AMPK, PGC-1α, and sirtuins.
- Integration of evidence on systemic factors like myokines, gut microbiota, and thyroid hormones influencing hepatic mitochondria.
Main Results:
- Exercise activates key regulators (AMPK, PGC-1α, sirtuins) to promote mitochondrial biogenesis, fatty acid oxidation, and mitophagy.
- Exercise suppresses hepatic lipogenesis and oxidative injury, reducing steatosis, inflammation, and fibrogenesis.
- Systemic signals from skeletal muscle, gut, and thyroid converge to enhance hepatic mitochondrial function and metabolic flexibility.
Conclusions:
- Exercise acts as a systems-level stimulus for hepatic mitochondrial remodeling, improving metabolic health in MASLD/MASH.
- These adaptations enhance hepatocellular resilience, insulin sensitivity, and metabolic flexibility.
- This framework supports precision exercise prescriptions and combination therapies targeting mitochondrial health for MASLD/MASH.
