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Introduction
Skeletal muscle development is a strictly regulated process involving the specification of mesodermal precursors into myoblasts, following the differentiation and fusion of these cells into multinucleated myotubes. Myogenic regulatory factors (MRFs) play a specific role in muscle fusion during differentiation (1,2). Among the MRFs, basic helix-loop-helix (bHLH) transcription factors, myogenic differentiation 1 (MyoD), myogenic factor 5 (Myf5), myogenin and MRF4 are critical to muscle formation. MyoD and Myf5 are required for the formation of skeletal muscle and play unique roles in the development of epaxial and hypaxial muscle, respectively (3,4). These two MRFs enable the differentiation of myogenic progenitors into myoblasts, which differentiate into myotubes by myogenin. Moreover, MyoD promotes myoblast differentiation by regulating the cell cycle (5). MRF4 is important for blocking the transcription of muscle-specific promoters, and enabling the growth and proliferation of skeletal muscle progenitors prior to differentiation. Myogenin activates MRF4 transcription independently, and synergistically stimulates the MRF4 promoter (6).
Ursolic acid, a natural pentacyclic triterpenoid carboxylic acid (7), is abundantly found in a number of fruits and plants, including apples (a major compound of apple peels), cranberries, basil, peppermint and rosemary (8). It has been used for pharmaceutical, cosmetic and food preparations. Of note, ursolic acid has garnered much attention as a therapeutic compound in a number of diseases, such as cancer (9), diabetes (10), Alzheimer’s disease (11) and obesity (12), due to its anti-inflammatory and antitumor properties. Moreover, this triterpene has been reported to increase the insulin-induced phosphorylation of Akt, a serine/threonine-specific protein kinase, that plays a key role in multiple cellular processes, such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration (13). In skeletal muscle, Akt has been reported to inhibit muscle atrophy and promote muscle hypertrophy, which is linked to muscle protein synthesis. Recently, Kunkel et al (14) demonstrated that ursolic acid enhanced skeletal muscle insulin/insulin-like growth factor 1 (IGF-I) signaling, leading to Akt activation, muscle hypertrophy and reduced adiposity and blood glucose levels in mice. Ursolic acid has also been shown to increase muscle mass through Akt activation in fed a mice high-fat diet (15). In the same study, ursolic acid exhibited a beneficial effect by not only increasing skeletal muscle mass, but also increasing energy expenditure, leading to reduced obesity, improved glucose...