Proteomic Profile of Skeletal Muscles and Liver in a Dexamethasone-Induced Atrophy Model: Insights into the Role of β-Hydroxy-β-Methylbutyrate on Contractile and Metabolic Protein

First study to characterize the proteomic alterations induced by β-Hydroxy-β-Methylbutyrate in combination with Dexamethasone. Evaluation of β-Hydroxy-β-Methylbutyrate in a severe glucocorticoid-induced muscle atrophy model. Analysis focused on white (fast-twitch) skeletal muscle, which is preferentially affected by glucocorticoid-induced atrophy. Although some effects of glucocorticoids are necessary for metabolic responses during stress, chronic exposure to high levels of these hormones can cause side effects such as hyperglycemia, insulin resistance, and muscle atrophy. Elevated glucocorticoid levels are observed in several clinical conditions, and their exogenous administration, such as high-dose dexamethasone treatments, is included in many clinical protocols. In this context, the supplement β-Hydroxy-β-methylbutyrate (HMB) emerges as a promising approach to counteract side effects its anticatabolic action. Therefore, the aim of this study was to evaluate the protein profile in the muscles and liver of rats treated with HMB in response to a model of severe muscle atrophy induced by dexamethasone. A total of 24 male Wistar rats, 60 days old, were used and distributed into the following groups: (1) Placebo Experimental Group (PEG), n = 8, treated only with saline solution; (2) Dexamethasone Experimental Group (DEG), n = 8, treated with intraperitoneal Dexamethasone injection (1 mg/kg/day); and (3) Dexamethasone + HMB Experimental Group (DEHG), n = 8, treated with intraperitoneal Dexamethasone injection (1 mg/kg/day) and gavaged with HMB (0.3 g/kg/day). After 10 days of treatment, the animals were euthanized for collection of the Soleus, Extensor Digitorum Longus (EDL) muscles, and liver, followed by protein processing and identification. In the Soleus muscle, when comparing DEG vs. PEG, proteins such as Myosin heavy chain 2, Myosin-4, Myosin-6, and Myosin-7 showed decreased expression in DEG compared to PEG. Comparing PEG vs. DEHG also showed a decrease in myosin expression in DEHG, but only Myosin-6 and Myosin-7 were reduced among the identified isoforms. In the EDL muscle, both DEG and DEHG showed reduced levels of all identified myosin subtypes. However, when comparing DEG and DEHG, the only myosin isoform preserved in DEHG compared to DEG was Myosin heavy chain 2. In the liver, dexamethasone treatment impaired glucose uptake, altered the Cytochrome P450 system, and reduced mitochondrial function, as reflected by reduced ATP levels. In conclusion, dexamethasone induced the loss of contractile proteins (myosins) in both muscles. The HMB dosage used in this study partially prevented myosin loss in the Soleus muscle but did not inhibit myosin loss in the EDL muscle. In the liver, dexamethasone induced changes in several proteins related to glucose metabolism; however, HMB was unable to attenuate dexamethasone-induced hepatic glycogenolysis.