Abstract
Lactate is a metabolic substrate mainly produced in muscles, especially during exercise. Recently, it was reported that lactate affects myoblast differentiation; however, the obtained results are inconsistent and the in vivo effect of lactate remains unclear. Our study thus aimed to evaluate the effects of lactate on myogenic differentiation and its underlying mechanism. The differentiation of C2C12 murine myogenic cells was accelerated in the presence of lactate and, consequently, myotube hypertrophy was achieved. Gene expression analysis of myogenic regulatory factors showed significantly increased myogenic determination protein (MyoD) gene expression in lactate-treated cells compared with that in untreated ones. Moreover, lactate enhanced gene and protein expression of myosin heavy chain (MHC). In particular, lactate increased gene expression of specific MHC isotypes, MHCIIb and IId/x, in a dose-dependent manner. Using a reporter assay, we showed that lactate increased promoter activity of the MHCIIb gene and that a MyoD binding site in the promoter region was necessary for the lactate-induced increase in activity. Finally, peritoneal injection of lactate in mice resulted in enhanced regeneration and fiber hypertrophy in glycerol-induced regenerating muscles. In conclusion, physiologically high lactate concentrations modulated muscle differentiation by regulating MyoD-associated networks, thereby enhancing MHC expression and myotube hypertrophy in vitro and, potentially, in vivo.
Highlights
Decreases in muscle volume contribute to a number of adverse health outcomes, such as disability and frailty in the elderly [1,2] and various chronic diseases, including diabetes and obesity [3,4]
We initially examined the effect of lactate on the morphological differentiation of C2C12 myoblasts
The data obtained this study demonstrated that sustained treatment with lactate enhanced myogenic differentiation and gene expression of fast-twitch-type myosin heavy chain (MHC)
Summary
Decreases in muscle volume contribute to a number of adverse health outcomes, such as disability and frailty in the elderly [1,2] and various chronic diseases, including diabetes and obesity [3,4]. Activated satellite cells proliferate and differentiate into mature muscle cells, regenerating newly formed myofibers to achieve muscle remodeling This regenerative process is orchestrated by the expression of myogenic regulatory factors (MRFs), a group of bHLH transcription factors including myogenic factor 5 (Myf5), myogenic determination protein (MyoD), and myogenin [6,7]. Oishi et al [24] showed that the treatment of C2C12 cells with lactate resulted in increases in myogenin and the activation of p70S6K, a critical regulator of muscle protein synthesis Both investigators conducted in vivo studies, using human or mouse muscles harvested after exercise training, to confirm their results. Our findings suggested that lactate plays a pathophysiological role in myogenic precursor cells via MyoD, a member of the MRFs, which contrasts with the results of previous studies
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