Related Experiment Video
Updated: May 31, 2026
Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry
Published on: October 4, 2024
Reductions in RIP140 are not required for exercise- and AICAR-mediated increases in skeletal muscle mitochondrial
Bruce C Frier1, Chad R Hancock, Jonathan P Little
1Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
Abstract:
Receptor interacting protein 1 (RIP140) has recently been demonstrated to be a key player in the regulation of skeletal muscle mitochondrial content. We have shown that β-guanadinopropionic acid (β-GPA) feeding reduces RIP140 protein content and mRNA levels concomitant with increases in mitochondrial content (Williams DB, Sutherland LN, Bomhof MR, Basaraba SA, Thrush AB, Dyck DJ, Field CJ, Wright DC. Am J Physiol Endocrinol Metab 296: E1400-E1408, 2009). Since β-GPA feeding reduces high-energy phosphate levels and activates AMPK, alterations reminiscent of exercise, we hypothesized that exercise training would reduce RIP140 protein content. We further postulated that an acute bout of exercise, or interventions known to induce the expression of mitochondrial enzymes or genes involved in mitochondrial biogenesis, would result in decreases in nuclear RIP140 content. Two weeks of daily swim training increased markers of mitochondrial content in rat skeletal muscle independent of reductions in RIP140 protein. Similarly, high-intensity exercise training in humans failed to reduce RIP140 content despite increasing skeletal muscle mitochondrial enzymes. We found that 6 wk of daily 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) injections had no effect on RIP140 protein content in rat skeletal muscle while RIP140 content from LKB1 knockout mice was unaltered despite reductions in mitochondria. An acute bout of exercise, AICAR treatment, and epinephrine injections increased the mRNA levels of PGC-1α, COXIV, and lipin1 independent of decreases in nuclear RIP140 protein. Surprisingly these interventions increased RIP140 mRNA expression. In conclusion our results demonstrate that decreases in RIP140 protein content are not required for exercise and AMPK-dependent increases in skeletal muscle mitochondrial content, nor do acute perturbations alter the cellular localization of RIP140 in parallel with the induction of genes involved in mitochondrial biogenesis.
Insights
Exercise and AMPK activation do not require reduced RIP140 protein for skeletal muscle mitochondrial growth. Acute exercise and metabolic interventions increase mitochondrial genes without decreasing RIP140 protein.
Area of Science:
- Exercise Physiology
- Molecular Biology
- Mitochondrial Biogenesis
Background:
- Receptor interacting protein 1 (RIP140) is implicated in regulating skeletal muscle mitochondrial content.
- Previous research showed β-guanadinopropionic acid (β-GPA) feeding reduces RIP140 and increases mitochondrial content, mimicking exercise effects.
Purpose of the Study:
- To investigate if exercise training reduces RIP140 protein content in skeletal muscle.
- To determine if acute exercise or metabolic interventions decrease nuclear RIP140 content alongside mitochondrial gene induction.
Main Methods:
- Rat models underwent swim training and AICAR injections.
- Human subjects performed high-intensity exercise.
- LKB1 knockout mice models were used.
- RIP140 protein and mRNA levels, mitochondrial markers, and gene expression (PGC-1α, COXIV, lipin1) were analyzed.
Main Results:
- Swim training and high-intensity exercise increased mitochondrial content/enzymes but did not reduce RIP140 protein.
- AICAR injections did not alter RIP140 protein in rats.
- LKB1 knockout mice showed unaltered RIP140 despite reduced mitochondria.
- Acute exercise, AICAR, and epinephrine increased mitochondrial gene mRNA but also increased RIP140 mRNA, without decreasing RIP140 protein.
Conclusions:
- Reduced RIP140 protein is not necessary for exercise or AMPK-dependent increases in skeletal muscle mitochondrial content.
- Acute exercise and metabolic interventions do not alter RIP140 cellular localization in parallel with mitochondrial biogenesis gene induction.
- RIP140 mRNA expression may increase following these interventions.
