N-acetyl-L-cysteine Prevents Lactate-Mediated PGC1-alpha Expression in C2C12 Myotubes

Nalbandian, Minas; Radák, Zsolt; Takeda, Masaki

doi:10.3390/biology8020044

Cited by 10 publications

(6 citation statements)

References 30 publications

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“…The results showed that ROS might act as mediators of lactate effect on autophagy. These results agree with previous studies in which ROS mediated the lactate up-regulation of PGC1-α in C2C12 (Nalbandian et al 2019), p38-MAPK signaling pathways in germ (Galardo et al 2014), and IL-8 expression in HUVEC cells (Végran et al 2011). ROS's nature mediating the autophagic effect of lactate in skeletal muscle cannot be determined from the present study.…”

Section: Discussionsupporting

confidence: 93%

Lactate regulates autophagy through ROS-mediated activation of ERK1/2/m-TOR/p-70S6K pathway in skeletal muscle

Nikooie

Moflehi

Zand

2021

J. Cell Commun. Signal.

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The role of autophagy and lysosomal degradation pathway in the regulation of skeletal muscle metabolism was previously studied. However, underlying molecular mechanisms are poorly understood. L‐lactate which is utilized as an energetic substrate by skeletal muscle can also augment genes expression related to metabolism and up‐regulate those being responsive to reactive oxygen species (ROS). Since ROS is the most important regulator of autophagy in skeletal muscle, we tested if there is a link between cellular lactate metabolism and autophagy in differentiated C2C12 myotubes and the gastrocnemius muscle of male wistar rats. C2C12 mouse skeletal muscle was exposed to 2, 6, 10, and 20 mM lactate and evaluated for lactate autophagic effects. Lactate dose‐dependently increased autophagy and augmented ROS generation in differentiated C2C12 myotubes. The autophagic effect of lactate deterred in N‐acetylcysteine presence (NAC, a ROS scavenger) indicated lactate regulates autophagy with ROS participation. Lactate‐induced up‐regulation of extracellular signal‐regulated kinase 1/2 (ERK1/2) through ROS was required to regulate the autophagy by lactate. Further analysis about ERK1/2 up‐ and downstream indicated that lactate regulates autophagy through ROS‐mediated the activation of ERK1/2/mTOR/p70S6K pathway in skeletal muscle. The in vitro effects of lactate on autophagy also occurred in the gastrocnemius muscle of male Wistar rats. In conclusion, we provided the lactate‐associated regulation evidence of autophagy in skeletal muscle by activating ROS‐mediated ERK1/2/mTOR/p70S6K pathway. Since the increase in cellular lactate concentration is a hallmark of energy deficiency, the results provide insight into a skeletal muscle mechanism to fulfill its enhanced energy requirement.

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Section: Discussionsupporting

confidence: 93%

Lactate regulates autophagy through ROS-mediated activation of ERK1/2/m-TOR/p-70S6K pathway in skeletal muscle

Nikooie

Moflehi

Zand

2021

J. Cell Commun. Signal.

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“…The idea of lactate being a signaling molecule has been tested in several models. In differentiated C2C12 cells (mouse immortalized myoblasts), culture with L-lactate increased the expression of PGC1-alpha (peroxisome proliferatoractivated receptor gamma coactivator 1-alpha), which is a transcription factor responsible for mitochondrial biogenesis (Nalbandian et al, 2019). Similarly, in differentiated L6 cells (immortalized rat myoblasts), culture with lactate increased the expression of PGC1-alpha as well as the expression of several genes related to metabolism like MCT1 (Hashimoto et al, 2007).…”

Section: A B Cmentioning

confidence: 99%

Lactate Metabolism and Satellite Cell Fate

2020

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Lactate is one of the metabolic products of glycolysis. It is widely accepted as an important energy source for many cell types and more recently has been proposed to actively participate in cell-cell communication. Satellite cells (SCs), which are adult skeletal muscle stem cells, are the main players of the skeletal muscle regeneration process. Recent studies have proposed a metabolic switch to increase glycolysis in activated SCs. Moreover, lactate has been shown to affect SCs and myoblasts in vivo and in vitro. In this short review, we describe how metabolic variations relate with SC fate (quiescence, activation, proliferation, migration, differentiation, fusion, and self-renewal), as well as discuss possible relationships between lactate as a metabolite and as a signaling molecule affecting SC fate.

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“…Moreover, treatment with allopurinol, an XO inhibitor, prevented the increase of PGC-1α and its target genes in the vastus lateralis muscle of rats after a single session of anaerobic exercise [ 102 ]. Lactate can stimulate mitochondrial biogenesis in cardiac and skeletal muscle [ 103 ], and recently, lactate-induced PGC-1α was shown to be blocked by antioxidant treatment, in C2C12 skeletal muscle cells [ 104 ], suggesting that a ROS can couple with lactate metabolism to stimulate PGC-1α production.…”

Section: The Role Of Ros In Physical Exercise Adaptationsmentioning

confidence: 99%

Exercise-Stimulated ROS Sensitive Signaling Pathways in Skeletal Muscle

et al. 2021

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Physical exercise represents a major challenge to whole-body homeostasis, provoking acute and adaptative responses at the cellular and systemic levels. Different sources of reactive oxygen species (ROS) have been described in skeletal muscle (e.g., NADPH oxidases, xanthine oxidase, and mitochondria) and are closely related to the physiological changes induced by physical exercise through the modulation of several signaling pathways. Many signaling pathways that are regulated by exercise-induced ROS generation, such as adenosine monophosphate-activated protein kinase (AMPK), mitogen activated protein kinase (MAPK), nuclear respiratory factor2 (NRF2), and PGC-1α are involved in skeletal muscle responses to physical exercise, such as increased glucose uptake, mitochondriogenesis, and hypertrophy, among others. Most of these adaptations are blunted by antioxidants, revealing the crucial role played by ROS during and after physical exercise. When ROS generation is either insufficient or exacerbated, ROS-mediated signaling is disrupted, as well as physical exercise adaptations. Thus, an understanding the limit between “ROS that can promote beneficial effects” and “ROS that can promote harmful effects” is a challenging question in exercise biology. The identification of new mediators that cause reductive stress and thereby disrupt exercise-stimulated ROS signaling is a trending on this topic and are covered in this current review.

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N-acetyl-L-cysteine Prevents Lactate-Mediated PGC1-alpha Expression in C2C12 Myotubes

Cited by 10 publications

References 30 publications

Lactate regulates autophagy through ROS-mediated activation of ERK1/2/m-TOR/p-70S6K pathway in skeletal muscle

Lactate regulates autophagy through ROS-mediated activation of ERK1/2/m-TOR/p-70S6K pathway in skeletal muscle

Lactate Metabolism and Satellite Cell Fate

Exercise-Stimulated ROS Sensitive Signaling Pathways in Skeletal Muscle

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