Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux

Abstract

Recent studies on mouse and human skeletal muscle (SM) demonstrated the important link between mitochondrial function and the cellular metabolic adaptation. To identify key compensatory molecular mechanisms in response to chronic mitochondrial distress, we analyzed mice with ectopic SM respiratory uncoupling in uncoupling protein 1 transgenic (UCP1-TG) mice as model of muscle-specific compromised mitochondrial function. Here we describe a detailed metabolic reprogramming profile associated with mitochondrial perturbations in SM, triggering an increased protein turnover and amino acid metabolism with induced biosynthetic serine/ 1-carbon/glycine pathway and the longevity-promoting polyamine spermidine as well as the trans-sulfuration pathway. This is related to an induction of NADPHgenerating pathways and glutathione metabolism as an adaptive mitohormetic response and defense against increased oxidative stress. Strikingly, consistent muscle retrograde signaling profiles were observed in acute stress states such as muscle cell starvation and lipid overload, muscle regeneration, and heart muscle inflammation, but not in response to exercise. We provide conclusive evidence for a key compensatory stresssignaling network that preserves cellular function, oxidative stress tolerance, and survival during conditions of increased SM mitochondrial distress, a metabolic reprogramming profile so far only demonstrated for cancer cells and heart muscle.-Ost, M., Keipert, S., van Schothorst, E. M., Donner, V., van der Stelt, I., Kipp, A. P., Petzke, K.-J., Jove, M., Pamplona, R., Portero-Otin, M., Keijer, J., Klaus, S. Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux. FASEB J. 29, 1314-1328 (2015). www.fasebj.org Key Words: amino acid metabolism • metabolic reprogramming • mitochondrial myopathy • oxidative stress tolerance • polyamines SKELETAL MUSCLE (SM) WASTING, or atrophy, occurs as a physiologic response to muscle disuse, fasting, starvation, and aging; it also occurs in a wide range of systemic diseases, including cancer, denervation, and diabetes mellitus (1-4). Numerous studies connected alterations in mitochondrial function to muscle atrophy, focusing on mitochondrial respiratory chain dysfunction or formation of reactive oxygen species (ROS) (5), as mitochondria represent an important site of cellular ROS production (6). Mitochondria are key dynamic organelles that not only provide ATP via oxidative phosphorylation but also are involved in the cellular integrated stress response (7) and in mitohormesis, a molecular adaptation and retrograde response resulting in stress resistance (8).We previously demonstrated in a transgenic mouse model with alterations in SM mitochondrial function (uncoupling protein 1 [UCP1] transgenic [TG] mice [UCP1-TG], with ectopic expression of UCP1 in SM) an elevated endogenous antioxidant defense system, induced integrated stress response but also compromised mitochondrial respiratory chain capacity (9) and a strong reduction in SM mass (10). In contrast...

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

“…Further, muscle glutathione peroxidase (GPx) activity as marker of cellular oxidative stress response remained increased in TG/FGF21 À/À mice ( Figure 5E). 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 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).…”

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

“…This was preserved also with increasing NZO genetic background which could possibly account for the decreased lean body mass to which muscle contributes to a great extent. Furthermore, SM mitochondrial uncoupling induces a metabolic remodeling as a result of compensatory stress-signaling network that preserves cellular function as part of a muscle mitohormesis program (Keipert et al 2013a;Ost et al 2015). The induction of key genes linked to this remodeling was not attenuated but rather increased in N2-tg mice compared to F1-tg mice showing clearly that the normal response to skeletal muscle mitochondrial uncoupling is preserved in mice with increasing NZO genetic background.…”

“…3). These are two key genes of the serine, onecarbon, glycine (SOG) pathway which is induced by SM mitochondrial stress (Ost et al 2015). UCP1 expression in SM has been shown to induce a fiber type switch from glycolytic type II fibers toward oxidative type I fibers (Couplan et al 2002;Ost et al 2014).…”

“…Overall, UCP1 expression in skeletal muscle thus leads to beneficial effects on glucose homeostasis. This healthy metabolic phenotype of UCP1-tg mice is associated with the induction and secretion of fibroblast growth factor 21 (FGF21) from skeletal muscle (Keipert et al 2014) which in turn linked to a metabolic remodeling program in skeletal muscle due to muscle mitohormesis (Ost et al 2015). Overexpression and systemic administration of FGF21 has been shown to reduce obesity and improve glucose homeostatic in mice (Coskun et al 2008;Inagaki et al 2008;Kharitonenkov et al 2005;Zhang et al 2012).…”