# PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease

## TL;DR

This study shows that different muscles in the same person respond differently to mitochondrial disease, with eye muscles atrophying due to abnormal nutrient responses involving PDK4.

## Contribution

The study reveals that PDK4 activation in eye muscles leads to non-optimal lipid metabolism, explaining muscle atrophy in mitochondrial disease.

## Key findings

- Large muscles upregulate glycolysis and anabolic metabolism, while eye muscles inhibit glucose oxidation via PDK4.
- Eye muscles switch to fatty acid oxidation and lipid accumulation, which is detrimental in mitochondrial disease.
- Mitophagy is stalled in both muscle types, contributing to disease progression.

## Abstract

Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual—extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles—respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.

We used a mouse model for mitochondrial myopathy (“deletor”), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single‐nuclear RNA‐sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito‐QC marker mice crossed to deletors.

In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one‐carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl‐CoA synthesis and fatty‐acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.‐ Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.

Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non‐optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non‐optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.

Mitochondrial disease triggers opposite responses in different muscles. Mitochondrial integrated stress response (ISRmt) and aerobic glycolysis characterize large muscles. Eye muscles show no ISRmt but activate PDK4—inhibitor of glucose oxidation—thereby upregulating beta‐oxidation, which is non‐optimal in mitochondrial disease and can explain eye muscle atrophy in mitochondrial disease.