Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Abstract

Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells.Satellite cells, which are among the most abundant well defined adult stem cell types in skeletal muscle, play functionally important roles in postnatal growth, repair, and the regeneration of skeletal muscle (1-6). Because of their powerful ability to regenerate in vivo in response to muscle damage and various stimuli, satellite cells represent important targets for the treatment of muscular diseases (7-10). The recent development of stem cell-based regenerative medicine strategies has brought enormous interest in the discovery of regulatory factors capable of controlling satellite cell functions, such as activation, proliferation, differentiation, and self-renewal (11-13). Identification of such factors is expected to not only improve our understanding of the regulatory mechanisms that govern satellite cell functions, but also to facilitate the development of stem cell-based therapies for the treatment of muscular dystrophy or other chronic diseases associated with muscle wasting.Recent studies demonstrating a close correlation between cell proliferation and metabolic alterations in various tumor types have drawn attention to the significance of intrinsic small metabolites as signaling molecules responsible for regulating various cellular activities (14, 15). Although only a very limited number of such metabolites have been identified to date, accumulating evidence suggests that these metabolites can be oncogenic and alter cell signaling through epigenetic regulation. For example, 2-hydroxyglutarate (2-HG), 4 succinate, and fumarate, which are the best characterized small metabolites with oncogenic function, have come to be regarded as oncometabolites (16 -19). In tumor cells, 2-HG is generated by mutant forms of isocitrate dehydrogenase (IDH1 and IDH2) (20 -23), whereas succinate and fumarate accumulate via mutant forms of succinate dehydrogenase and fumarate hydratase, respectively (24 -27). It has been clearly demonstrated that increases in the levels of these oncometabolites play causal roles in tumorigenesis (26 -34). Recent studies of the molecular mechanisms underlying their action have revealed that 2-HG and elevated levels of succinate ...

A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice

“…This suggests that the KD maximizes and preserves forelimb grip strength with age. There is evidence that the ketone body acetoacetate plays an important role as a signaling molecule in muscle cells independent of its metabolic effects (Zou et al, 2016). Acetoacetate has been shown to improve muscular dystrophy outcomes and accelerate muscle regeneration, suggesting that it may be an important player in attenuating age-related decline in muscle function.…”

Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation

“…; Zou et al . ). Moreover, therapeutic roles for KBs have long been proposed in a variety of disease states including aberrant glucose metabolism, genetic myopathies, hypoxic states and neurodegenerative pathologies (Veech, ).…”

“…Noteworthy for the present review is the recent identification of AcAc as a regulator of skeletal muscle satellite cell proliferation and muscle regeneration (Zou et al . ), and βHB as an inhibitor of HDACs (Shimazu et al . ) and the NLRP3 inflammasome (Youm et al .…”

Ketone ester supplementation blunts overreaching symptoms during endurance training overload

“…) and glucose depletion (Robinson & Williamson, ), and stimulation of muscle regeneration or remodelling by enhancing satellite cell activation and differentiation (Zou et al . ). Moreover, ketone bodies directly regulate a range of putative factors involved in the development of overtraining, such as autonomic neural output, inflammation and oxidative stress (Kimura et al .…”

“…Ketone bodies, namely D-β-hydroxybutyrate (D-βHB), acetoacetate (AcAc) and acetone, are fatty acid-derived compounds that can serve as an alternative energy substrate for active metabolic tissues including brain (Owen et al 1967), heart (Aubert et al 2016) or skeletal muscles (Balasse & Féry, 1989) under conditions of metabolic stress (Johnson et al 1969;Cahill, 1976). Aside from their role in energy supply, ketone bodies also can play a role in metabolic regulation by inhibiting muscle proteolysis (Thomsen et al 2018) and glucose depletion (Robinson & Williamson, 1980), and stimulation of muscle regeneration or remodelling by enhancing satellite cell activation and differentiation (Zou et al 2016). Moreover, ketone bodies directly regulate a range of putative factors involved in the development of overtraining, such as autonomic neural output, inflammation and oxidative stress (Kimura et al 2011;Puchalska & Crawford, 2017).…”