Muscle Protein Ankyrin-B Controls Mitochondrial Function and Exercise Endurance

Scientists have identified ankyrin-B as a critical regulator of mitochondrial dynamics in skeletal muscle, with direct implications for exercise capacity and metabolic health. This scaffolding protein, encoded by the ANK2 gene, has been linked to cardiometabolic syndrome in humans, but its specific role in muscle function remained unclear.

Researchers created mice lacking ankyrin-B specifically in skeletal muscle and subjected them to comprehensive exercise testing. The results were striking: these mice showed significantly reduced endurance capacity, achieving lower maximum velocities on treadmill tests and becoming exhausted faster than control mice. During voluntary wheel running, they consistently ran slower, covered shorter distances, and took longer breaks.

At the cellular level, muscle fibers lacking ankyrin-B displayed dramatically altered mitochondrial structure and function. The mitochondria became enlarged and hyperconnected, indicating impaired fission (division) processes. This structural abnormality correlated with reduced fatty acid oxidation capacity and increased oxidative stress. The researchers found that ankyrin-B directly interacts with and helps recruit key fission machinery, including DRP1 and its receptors, to mitochondrial division sites.

Interestingly, despite these exercise deficits, the mice maintained normal body weight, glucose tolerance, and insulin sensitivity. This suggests that ankyrin-B's role in muscle is specifically related to exercise adaptation rather than basic metabolic homeostasis. The protein appears essential for the metabolic flexibility that allows muscles to switch between fuel sources during energetic stress.

These findings reveal a previously unknown pathway connecting cellular scaffolding proteins to mitochondrial dynamics and exercise performance, potentially opening new therapeutic targets for improving muscle function and endurance capacity.