[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [General pathology](https://durgical.com/en/general-pathology/) › [Peripheral nerve and skeletal muscle](https://durgical.com/en/general-pathology/areas/nerve-muscle/) › Metabolic and mitochondrial myopathies

# Metabolic and mitochondrial myopathies

- Lesion

When muscle cannot burn glycogen, fat or oxygen properly, it cramps, breaks down with exercise or weakens slowly; mitochondria give ragged red fibres.

Updated Nov 12, 2026

## Key points

- McArdle (GSD V): myophosphorylase deficiency; cramps and myoglobinuria with short intense exercise; second wind; flat lactate on forearm test.
- Pompe (GSD II): acid alpha-glucosidase, lysosomal; infant cardiomegaly, macroglossia, hypotonia; adults: proximal and respiratory weakness; enzyme replacement exists.
- CPT II deficiency: commonest cause of recurrent rhabdomyolysis in adults, after prolonged exercise, fasting, cold or fever.
- Primary carnitine deficiency: lipid storage myopathy, cardiomyopathy, hypoketotic hypoglycaemia.
- Mitochondrial: ragged red fibres (Gomori trichrome), COX-negative fibres, maternal inheritance and heteroplasmy for mtDNA mutations.
- MELAS (stroke-like episodes, lactic acidosis), MERRF (myoclonic epilepsy), CPEO and Kearns-Sayre (ophthalmoplegia, ptosis, heart block).

## What it is

Inborn errors of muscle energy metabolism fall into three groups. Glycogen storage diseases block glycogen use: McArdle disease (myophosphorylase deficiency) causes exercise cramps, the 'second wind' and myoglobinuria; Pompe disease (acid maltase, a lysosomal enzyme) causes infantile cardiomyopathy with hypotonia or a later limb-girdle and respiratory myopathy. Lipid disorders, such as carnitine palmitoyltransferase II deficiency and primary carnitine deficiency, cause rhabdomyolysis after prolonged exercise or fasting, or lipid storage myopathy. Mitochondrial myopathies from mitochondrial or nuclear DNA mutations show ragged red fibres and COX-negative fibres, and are part of syndromes like MELAS, MERRF and chronic progressive external ophthalmoplegia.

## Structure

- McArdle: subsarcolemmal glycogen blebs, absent phosphorylase on histochemistry.
- Pompe: vacuoles full of PAS-positive glycogen inside lysosomes (acid phosphatase positive).
- Lipid myopathy: excess lipid droplets in type I fibres on oil red O stain.
- Mitochondrial: ragged red fibres from subsarcolemmal clumps of abnormal mitochondria; paracrystalline inclusions on electron microscopy; COX-negative, SDH-positive fibres.

## Step by step

- Muscle uses glycogen for short, intense effort and fatty acids for prolonged, low-intensity effort, all ending in mitochondrial oxidation.
- A block in glycogen breakdown starves fibres during sprint-type exercise.
- A block in fatty acid transport (CPT II, carnitine) starves fibres during long exercise or fasting.
- Energy failure collapses ion gradients and fibres necrose, releasing myoglobin.
- In mitochondrial disease, fibres with a high load of mutant mtDNA lose oxidative phosphorylation and proliferate abnormal mitochondria.

## Energy-failure myopathies by fuel

| Fuel blocked | Example | Trigger | Biopsy |
| --- | --- | --- | --- |
| [Glycogen (cytoplasmic)](https://durgical.com/en/conditions/mcardle-disease/) | McArdle disease | Brief intense exercise | Absent myophosphorylase; glycogen excess |
| [Glycogen (lysosomal)](https://durgical.com/en/conditions/pompe-disease/) | Pompe disease | Progressive weakness | Lysosomal glycogen vacuoles |
| [Fatty acids](https://durgical.com/en/conditions/carnitine-palmitoyltransferase-ii-deficiency/) | CPT II deficiency | Prolonged exercise, fasting, fever | Often normal between attacks |
| [Carnitine](https://durgical.com/en/conditions/primary-carnitine-deficiency/) | Primary carnitine deficiency | Fasting | Lipid storage in type I fibres |
| [Oxidative phosphorylation](https://durgical.com/en/conditions/melas/) | MELAS, MERRF, CPEO | Variable | Ragged red and COX-negative fibres |

## Clinical notes

- Recurrent dark urine after exercise points to a metabolic myopathy; the timing (short burst vs long effort) suggests glycogen vs lipid.
- Mitochondrial disease affects many organs with high energy needs: brain, eyes, heart, ears, kidney and endocrine glands.
- Lactate is often raised in blood and CSF in mitochondrial disease.

## Memory aid

Sprint and cramp: glycogen; marathon and dark urine: fat; ragged red and maternal: mitochondria.

## Test yourself

Think of the answer, then tap the question to see it.

## Which enzyme is missing in McArdle disease?

Muscle glycogen phosphorylase (myophosphorylase).

## What is the most common inherited cause of recurrent rhabdomyolysis after prolonged exercise in adults?

Carnitine palmitoyltransferase II deficiency.

## What are ragged red fibres?

Fibres with subsarcolemmal accumulations of abnormal mitochondria, red on Gomori trichrome.

## Why are mitochondrial DNA diseases inherited from the mother?

Mitochondria, and their DNA, come from the egg.

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## Elsewhere in DurgiPedia

- [Glycogen metabolism](https://durgical.com/en/biochemistry/pathways/glycogen-metabolism/)
- [Carnitine shuttle](https://durgical.com/en/biochemistry/topics/carnitine-shuttle/)
- [Electron transport chain and oxidative phosphorylation](https://durgical.com/en/biochemistry/pathways/electron-transport-chain-and-oxidative-phosphorylation/)

## Connections

## Related 3

- [Nonclassic inheritance: repeat expansions, mitochondrial genes, imprinting, mosaicism](https://durgical.com/en/general-pathology/nonclassic-inheritance-repeat-expansions-mitochondrial-genes-imprinting-mosaicis/)
- [Reading a muscle biopsy: neurogenic vs myopathic](https://durgical.com/en/general-pathology/reading-a-muscle-biopsy-neurogenic-vs-myopathic/)
- [Toxic and endocrine myopathies and rhabdomyolysis](https://durgical.com/en/general-pathology/toxic-and-endocrine-myopathies-and-rhabdomyolysis/)

## Related conditions 6

- [McArdle disease (glycogen storage disease type V)](https://durgical.com/en/conditions/mcardle-disease/)
- [Pompe disease (glycogen storage disease type II)](https://durgical.com/en/conditions/pompe-disease/)
- [Carnitine palmitoyltransferase II (CPT-II) deficiency](https://durgical.com/en/conditions/carnitine-palmitoyltransferase-ii-deficiency/)
- [Primary carnitine deficiency](https://durgical.com/en/conditions/primary-carnitine-deficiency/)
- [MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)](https://durgical.com/en/conditions/melas/)
- [Rhabdomyolysis](https://durgical.com/en/conditions/rhabdomyolysis/)

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Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.

Sources: [Glycogen storage disease type V: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/glycogen-storage-disease-type-v/) (MedlinePlus, US National Library of Medicine, 2025); [Pompe disease: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/pompe-disease/) (MedlinePlus, US National Library of Medicine, 2025); [Mitochondrial Diseases: MedlinePlus](https://medlineplus.gov/mitochondrialdiseases.html) (MedlinePlus, US National Library of Medicine, 2025).

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Representative model, for educational purposes only.

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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/general-pathology/metabolic-and-mitochondrial-myopathies/