Simplifying the Diagnosis of Mitochondrial Myopathy

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports no financial relationships relevant to this field of study.

Synopsis: Fibroblast growth factor 21, an important regulator of glucose and lipid metabolism in muscle, is strikingly elevated in the serum of patients with mitochondrial respiratory chain deficiencies.

Source: Suomalainen A, et al. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: A diagnostic study. Lancet Neurol 2011;10:806-818.

Mitochondrial cytopathies, disorders of the mitochondrial respira- tory chain, are multisystem disorders, most commonly affecting the peripheral nervous system, presenting as myopathy, but also the central nervous system, endocrine glands, myocardium, eyes, ears, gastrointestinal tract, kidneys, bone marrow, and skin. Myopathy may present at any age, as an isolated syndrome or as one component of a multisystem disorder, with clinical features including chronic progressive external ophthalmoplegia, proximal myopathy, muscle pain, and rhabdomyolysis. Diagnosis is challenging, often requiring both histological and histochemical analysis of muscle tissue to detect ragged-red fibers, subsarcolemmal accumulation of mitochondria, and a mosaic pattern of cytochrome c oxidase (COX) activity, and also necessitating mitochondrial DNA sequencing and nuclear and mitochondrial gene screening. A simpler test may now be at hand.

Fibroblast growth factor 21 (FGF-21), important in the regulation of glucose and lipid metabolism, is a protein whose serum and skeletal muscle concentrations are raised in mice with mitochondrial respiratory chain deficiencies. To determine if this is also true in humans, retrospective measurement of FGF-21 was undertaken in 67 patients, comprising 41 adults and 26 children, whose mitochondrial disorder was confirmed either by DNA analysis (n = 63) or on biochemical or histological analysis (n = 4). Results were compared to FGF-21 levels in 74 healthy and 34 disease controls, age-matched wherever possible. Statistical analysis included the Mann-Whitney U test, Spearman's rank correlation coefficient, and multivariate regression analyses, using two-sided P values with a significance level of P < 0.05.

Mean serum FGF-21 concentration was 76 pg/mL in the healthy control group, and did not differ by age or sex. It was 10-fold higher in adults, and an average of 26-fold higher in children, with respiratory chain deficiencies affecting muscle, including complex I, III, or IV deficiency; Alpers' hepatoencephalopathy; or infantile COX deficiency. FGF-21 concentrations were not raised in patients with muscular dystrophies. Sensitivity and specificity of FGF-21 were more than 90% for identifying mitochondrial disease affecting skeletal muscle, and FGF-21 was better than other conventional biomarkers, including lactate, pyruvate, lactate-to-pyruvate ratio, and creatine kinase, for correctly identifying muscle manifesting respiratory chain disorders. Only 3% of the correct diagnoses would have been missed using serum FGF-21 concentrations, whereas 38% would have been missed using lactate and pyruvate, 54% using lactate-to-pyruvate ratio, and 61% using creatine kinase. Serum FGF-21 concentration appears to be the best initial diagnostic test for patients with suspected respiratory chain deficiencies primarily affecting muscle.


A potent regulator of metabolism, recombinant FGF-21, when administered to rodents and monkeys, produces weight loss, lowering of triglyceride levels, and anti-hyperglycemic effects. How? Evidence suggests it enhances mitochondrial oxidation in adipocytes by activating AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). FGF-21 increases AMPK phosphorylation in mice adipocytes, and increases cellular NAD+ levels, resulting in SIRT1 activation. AMPK and SIRT1 activation induce metabolic genes, and increase oxygen consumption and citrate synthase activity. Hence, FGF-21 regulates mitochondrial activity, enhancing oxidative capacity, through AMPK–SIRT1-dependent mechanisms in adipocytes.1


1. Chau MD, et al. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc Natl Acad Sci 2010;107:12553-12558.