The authors wish to note the following: "Using studies of IgG hydrolyzed by the streptococcal glycan hydrolyzing enzyme EndoS, we found that treatment of mice with hydrolyzed IgG blocked antibody mediated arthritis. As an explanation for this observation, we suggested that EndoS-hydrolyzed IgG per se dominantly blocks local immune complex formation."With new data from our own follow up experiments, we have now found that this conclusion was incorrect."Our new data shows that injection of EndoS is much more potent in vivo than we could logically anticipate, as i.v. injection of doses containing less than 0.1 μg EndoS mixed with IgG suppressed arthritis using the same model as the one reported in the initial paper (collagen antibody-induced arthritis). We previously excluded the possibility that contaminating EndoS could play a role, as this contaminating amount was not detected using standard methods in the hydrolyzed IgG fraction we used in the experiments. Furthermore, much higher doses of EndoS injected in the same mouse strain as a control experiment did not affect collagen induced arthritis in earlier experiments. The correct interpretation of our collective data is that EndoS operates very potently in vivo on an immune complex-mediated disease, possibly by accumulating within immune complexes.

Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.

Summary Neuromuscular disorders with defects in the mitochondrial ATP generating system affect a large number of children and adults worldwide, but remain without treatment. We used a mouse model of mitochondrial myopathy, caused by a cytochrome c oxidase deficiency, to evaluate the effect of induced mitochondrial biogenesis on the course of the disease. Mitochondrial biogenesis was induced either by transgenic expression of peroxisome proliferator activated receptor γ (PPARγ) coactivator α (PGC-1α) in skeletal muscle or by administration of bezafibrate, a PPAR pan-agonist. Both strategies successfully stimulated residual respiratory capacity in muscle tissue. Mitochondrial proliferation resulted in an enhanced OXPHOS capacity per muscle mass. As a consequence, ATP levels were conserved resulting in a delayed onset of the myopathy and a markedly prolonged live span. Thus, induction of mitochondrial biogenesis through pharmacological or metabolic modulation of the PPAR/PGC-1α pathway promises to be an effective therapeutic approach for mitochondrial disorders.

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