Does β-Hydroxy-β-Methylbutyrate Have Any Potential to Support the Treatment of Duchenne Muscular Dystrophy in Humans and Animals?

Abstract

Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. The dystrophin gene is the largest gene and has a key role in skeletal muscle construction and function. Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans, mice, dogs, and cats. Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular condition causing progressive muscle weakness and premature death. β-hydroxy β-methylbutyrate (HMB) prevents deleterious muscle responses under pathological conditions, including tumor and chronic steroid therapy-related muscle losses. The use of HMB as a dietary supplement allows for increasing lean weight gain; has a positive immunostimulatory effect; is associated with decreased mortality; and attenuates sarcopenia in elderly animals and individuals. This study aimed to identify some genes, metabolic pathways, and biological processes which are common for DMD and HMB based on existing literature and then discuss the consequences of that interaction.

Keywords: DMD; HMB; biological process; genes; pathways.

Figure 2

Genes common for DMD and HMB—mTOR signaling pathways (based on Pathway Studio Web Mammalian [47,48,49,50,51,52,53,54]). Phosphatase and Tensin Homolog (PTEN), Regulatory Associated Protein of mTOR Complex 1 (RPTOR), CREB Regulated Transcription Coactivator 2 (TORC2), AKT Serine/Threonine Kinase 1 (AKT1), Forkhead Box O3 (FOXO3), Phosphatidylinositol (3)-trisphosphate (PIP3), AMP-activated Protein Kinase (AMPK), Phosphatidylinositol 3-kinase (PI3K), Mechanistic Target of Rapamycin (mTOR). The “+” symbol at the end of the arrow corresponds to stimulation, the “┤” symbol corresponds to inhibition.

Figure 3

Genes common for DMD and HMB—FOXO1 signaling pathways (based on Pathway Studio Web Mammalian [17,58,63,66,67,68,69]). AKT Serine/Threonine Kinase 1 (AKT1), Interleukin 6 (IL6), Caspase 3 (CASP3), Forkhead Box O1 (FOXO1), Phosphatidylinositol 3-kinase (PI3K), Sirtuin 1 (SIRT1). The “+” symbol at the end of the arrow corresponds to stimulation, the “┤” symbol corresponds to inhibition.

Figure 4

Genes common for DMD and HMB—insulin signaling pathway (based on Pathway Studio Web Mammalian [3,48,49,52,54,66,79,80]). Insulin (INS), Solute Carrier Family 2 Member 4 (SLC2A4), Solute Carrier Family 2 Member 2 (SLC2A2), Glycogen Synthase Kinase 3 Beta (GSK3B), Ribosomal Protein S6 Kinase B1(RPS6KB1), Insulin Receptor Substrate 2 (IRS2), AKT Serine/Threonine Kinase 1 (AKT1), Forkhead Box O1 (FOXO1), Forkhead Box O3 (FOXO3), Mechanistic Target of Rapamycin (mTOR), Phosphatidylinositol 3-kinase (PI3K). The “+” symbol at the end of the arrow corresponds to stimulation, the “┤” symbol corresponds to inhibition.

Figure 5

Myopathy-related genes and their interactions with HMB (based on Pathway Studio Web Mammalian). Tumor Necrosis Factor (TNF), Insulin-Like Growth Factor 1 (IGF1), BCL2 Associated X, Apoptosis Regulator (BAX), PPARG Coactivator 1 Alpha (PPARGC1A), Reactive Oxygen Species (ROS), Mechanistic Target of Rapamycin (mTOR). The “+” symbol at the end of the arrow corresponds to stimulation, the “┤” symbol corresponds to inhibition.

Figure 6

Rhabdomyolysis-related genes and their interactions with HMB (based on Pathway Studio Web Mammalian). F-Box Protein 32 (FBXO32), Tumor Necrosis Factor (TNF), Interleukin 6 (IL6), BCL2 Associated X, Apoptosis Regulator (BAX), Reactive Oxygen Species (ROS). The “+” symbol at the end of the arrow corresponds to stimulation, the “┤” symbol corresponds to inhibition.

Figure 7

Corticosteroids-related genes and their interactions with HMB (based on Pathway Studio Web Mammalian). Insulin-like Growth Factor (IGF), Leptin (LEP), Phosphoinositide 3-kinases (PI3K), Nuclear Factor Kappa B Subunit (NF-κB), Tumor Necrosis Factor (TNF), Transforming Growth Factor-Beta 1 (TGFB1), Growth Hormone (GH). The “+” symbol at the end of the arrow corresponds to stimulation, the “┤” symbol corresponds to inhibition.

Figure 8

Summary of the interactions of signaling pathways related to the development of DMD and mechanism of action of HMB in skeletal muscle cell (prepared based on Landi et al., 2019 [184]). Reactive Oxygen Species (ROS), Ketoisocaproate (KIC), Protein Kinase B (AKT), Mechanistic Target of Rapamycin (mTOR), Branched-Chain Ketoacid Dehydrogenase Complex (BCKDC), p70 Ribosomal S6 Kinase (P70S6K), Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 (4E-BP-1), Insulin-like Growth Factor 1 (IGF1), Growth Hormone (GH), Forkhead Box O1 (FOXO1), Forkhead Box O3 (FOXO3), Sirtuin 1 (SIRT1), Nuclear Factor Kappa B (NF-κB), Mitochondrial Branched-Chain Amino Acid Transaminase (mBCAT ). The “+” symbol corresponds to stimulation, the “x” symbol to inhibition. Black arrows pointing up and down indicate an increase or decrease in protein activity or process intensity, respectively.

Figure 1

Relevance network of genes, transcription factors, small molecules, functional classes, miRNA, and biological processes that are shared between DMD and HMB (based on Pathway Studio Web Mammalian). Tumor Necrosis Factor (TNF), Transforming Growth Factor Beta 1 (TGFB1), Insulin-Like Growth Factor 1 (IGF1), Myostatin (MSTN), AKT Serine/Threonine Kinase 1 (AKT1), Leptin (LEP), Interleukin 6 (IL6), Caspase 3 (CASP3), Mitogen-Activated Protein Kinase (MAPK14), Myogenic Differentiation (MyoD), Nitric Oxide Synthase (nNOS), Nuclear Factor Kappa B Subunit (NF-κB), Lactate Dehydrogenase (LDH), Interleukin 10 (IL10), Colony Stimulating Factor 3 (CSF3), Tripartite Motif Containing 63 (TRIM63), Interferon Gamma (IFNG), Forkhead Box O1 (FOXO1), Myogenic Factor 6 (MYF6), Caspase 3 (CASP3), BCL2 Associated X, Apoptosis Regulator (BAX), PPARG Coactivator 1 Alpha (PPARGC1A), Reactive Oxygen Species (ROS), Protein Kinase C (PKC), AMP-activated Protein Kinase (AMPK).