Mitochondrial myopathy induces a starvation-like response

Abstract

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.

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

“…In addition, the robust gene expression induction of the myokines Fgf21 and Gdf15, as shown previously in TG mice [10,34], could be confirmed, the latter similar in both TG and TG/ FGF21 À/À ( Figure 5F). Recently, we described a detailed profile of muscle metabolic remodeling [34] adding to the already established mitochondrial stress-related pseudo-starvation response [8]. In agreement with these studies, key markers related the serine, onecarbon, glycine (SOG) pathway (Psat1, Mthfd2) were induced in skeletal muscle of TG mice ( Figure 5G).…”

“…Nevertheless, although the different muscle-specific metabolic stress mouse models are based on distinct genetic manipulations [8e 10], they all show a common adaptive response including the induction of muscle ER stress-mediated FGF21 and amino acid biosynthetic pathways [34]. In the present study, we show that the common mitochondrial stress-related pseudo-starvation response [8,34], including key markers related to the serine, one-carbon, glycine (SOG) pathway, was still highly induced in TG/FGF21 À/À mice. This indicates that the muscle cell-autonomous metabolic remodeling occurs independently of endogenous FGF21, which needs to be confirmed in other described mitochondrial stress mouse models.…”

Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

“…Strikingly, the mRNA levels for myokines associated with mitochondrial myopathy and whole body energy homeostasis, FGF21 and GDF15 (15)(16)(17), are strongly induced in skeletal muscle (Fig. S4 C and D).…”

“…In mitochondrial myopathy, muscle mitochondrial stress is associated with the induction of the myokines fibroblast growth factor 21 (FGF21) (15,16) and growth differentiation factor 15 (GDF15) (17). Elevated FGF21 and GDF15 are associated with diabetes and glucose intolerance (18,19) but have been shown to reduce serum glucose and insulin levels (20).…”

La Finlande : un héritage génétique idéalement mis en valeur

“…La physiologie de ce dernier a largement bénéficié de la découverte des gènes correspondants en pathologie humaine. Par ailleurs, Anu Suomalainen [16], grande spécialiste de la mitochondrie, a également élargi ses recherches à la sphère neuromusculaire. Nombre de ces travaux ont été accomplis grâce aux collaborations initiées et poursuivies par des chercheurs finlandais avec l'ensemble de la communauté myologique.…”