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Muscle-building supplement β-hydroxy β-methylbutyrate stimulates the maturation of oligodendroglial progenitor cells to oligodendrocytes.

ABSTRACT: Oligodendrocytes are the myelinating cells in the CNS and multiple sclerosis (MS) is a demyelinating disorder that is characterized by progressive loss of myelin. Although oligodendroglial progenitor cells (OPCs) should be differentiated into oligodendrocytes, for multiple reasons, OPCs fail to differentiate into oligodendrocytes in MS. Therefore, increasing the maturation of OPCs to oligodendrocytes may be of therapeutic benefit for MS. The β-hydroxy β-methylbutyrate (HMB) is a muscle-building supplement in humans and this study underlines the importance of HMB in stimulating the maturation of OPCs to oligodendrocytes. HMB treatment upregulated the expression of different maturation markers including PLP, MBP, and MOG in cultured OPCs. Double-label immunofluorescence followed by immunoblot analyses confirmed the upregulation of OPC maturation by HMB. While investigating mechanisms, we found that HMB increased the maturation of OPCs isolated from peroxisome proliferator-activated receptor β^-/- (PPARβ^-/-) mice, but not PPARα^-/- mice. Similarly, GW6471 (an antagonist of PPARα), but not GSK0660 (an antagonist of PPARβ), inhibited HMB-induced maturation of OPCs. GW9662, a specific inhibitor of PPARγ, also could not inhibit HMB-mediated stimulation of OPC maturation. Furthermore, PPARα agonist GW7647, but neither PPARβ agonist GW0742 nor PPARγ agonist GW1929, alone increased the maturation of OPCs. Finally, HMB treatment of OPCs led to the recruitment of PPARα, but neither PPARβ nor PPARγ, to the PLP gene promoter. These results suggest that HMB stimulates the maturation of OPCs via PPARα and that HMB may have therapeutic prospects in remyelination.

SUBMITTER: Jana M

PROVIDER: S-EPMC11260247 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Muscle-building supplement β-hydroxy β-methylbutyrate stimulates the maturation of oligodendroglial progenitor cells to oligodendrocytes.

Jana Malabendu M Prieto Shelby S Gorai Sukhamoy S Dasarathy Sridevi S Kundu Madhuchhanda M Pahan Kalipada K

Journal of neurochemistry 20240228 7

Oligodendrocytes are the myelinating cells in the CNS and multiple sclerosis (MS) is a demyelinating disorder that is characterized by progressive loss of myelin. Although oligodendroglial progenitor cells (OPCs) should be differentiated into oligodendrocytes, for multiple reasons, OPCs fail to differentiate into oligodendrocytes in MS. Therefore, increasing the maturation of OPCs to oligodendrocytes may be of therapeutic benefit for MS. The β-hydroxy β-methylbutyrate (HMB) is a muscle-building ...[more]

PMID: 38419348

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Project description:β-Hydroxy-β-Methyl Butyrate (HMB) is a natural catabolite of leucine deemed to play a role in amino acid signaling and the maintenance of lean muscle mass. Accordingly, HMB is used as a dietary supplement by sportsmen and has shown some clinical effectiveness in preventing muscle wasting in cancer and chronic lung disease, as well as in age-dependent sarcopenia. However, the molecular cascades underlying these beneficial effects are largely unknown. HMB bears a significant structural similarity with Butyrate and β-Hydroxybutyrate (βHB), two compounds recognized for important epigenetic and histone-marking activities in multiple cell types including muscle cells. We asked whether similar chromatin-modifying actions could be assigned to HMB as well. Exposure of murine C2C12 myoblasts to millimolar concentrations of HMB led to an increase in global histone acetylation, as monitored by anti-acetylated lysine immunoblotting, while preventing myotube differentiation. In these effects, HMB resembled, although with less potency, the histone deacetylase (HDAC) inhibitor Sodium Butyrate. However, initial studies did not confirm a direct inhibitory effect of HMB on HDACs in vitro. β-Hydroxybutyrate, a ketone body produced by the liver during starvation or intense exercise, has a modest effect on histone acetylation of C2C12 cells or in vitro HDAC inhibitor activities, and, unlike Butyrate and HMB, did not interfere with myotube formation in a myoblast differentiation assay. Instead, βHB dramatically increased lysine β-hydroxybutyrylation (Kbhb) of histone tails, an epigenetic mark associated with fasting responses and muscle catabolic states. However, when C2C12 cells were exposed to βHB in the presence of equimolar HMB this chromatin modification was drastically reduced, pointing to a role for HMB in attenuating ketosis-associated muscle wasting. In conclusion, while their mechanistic underpinnings remain to be clarified, these preliminary observations highlight novel and potentially important activities of HMB as an epigenetic regulator and βHB antagonist in muscle precursor cells, to be further explored in their biomedical implications.

Project description:BackgroundFrailty is a key element in healthy ageing in which muscle performance plays a main role. Beta-hydroxy-beta-methylbutyrate (HMB) supplementation has shown favourable effects in modulating protein synthesis, improving muscle mass and function in interventional studies. Decreased age-related endogenous HMB levels have been shown in previous studies. The aim of the present study is to assess whether there is an association between endogenous plasma HMB levels and frailty.MethodsData from 1290 subjects (56.98% women; mean ± standard deviation age 74.6 ± 5.95 years) from the Toledo Study for Healthy Aging were obtained. Participants had their frailty status qualified according to Fried's Frailty Phenotype (FFP) score and the Frailty Trait Scale in its 12-domain version (FTS-12). Plasma HMB levels were analysed by an ultrahigh-performance liquid chromatography tandem mass spectrometry. Differences between groups (frail vs. non-frail) were tested using Mann-Whitney U test, Kruskal-Wallis test and chi-squared test. The association between HMB and frailty was assessed by multivariate linear and logistic regressions when frailty was analysed as continuous and binary, respectively. Models were adjusted by age, gender, comorbidity, body composition and protein intake.ResultsHMB levels were lower in those aged ≥75 years than in those aged 65-74 years, with an inverse linear relationship between age and HMB levels (β = -0.031; P = 0.018), mainly accounted by males (β = -0.062; P = 0.002). HMB levels were higher in men (0.238 ± 0.065 vs. 0.193 ± 0.051 ng/mL; P ≤ 0.001). HMB levels were significantly lower in frail than in non-frail individuals: 0.204 ± 0.058 versus 0.217 ± 0.063 ng/dL (P = 0.001) according to the FFP and 0.203 ± 0.059 versus 0.219 ± 0.063 ng/mL (P < 0.001) according to FTS-12. These differences showed a dose-dependent profile when we compared them by quintiles of HMB (P for trend: 0.022; 0.012 and 0.0004, respectively, for FFP, FTS-12 binary and FTS-12 continuous). Variables associated with low HMB levels were body mass index, strength, exhaustion and weight loss. Frailty was associated with HMB levels in all the adjusted models, including the fully adjusted ones, no matter the tool used (odds ratio: 0.45 [0.26, 0.77] for FFP and 0.36 [0.20, 0.63] for FTS-12 binary; β = -4.76 [-7.29, -2.23] for FTS-12 score). This association was also observed when the analyses were done by quintiles, showing such association since Q4 (FFP), Q2 (FTS-12 binary) and Q3 (FTS-12 score). The associations were observed in the whole sample and in each gender.ConclusionsThere is an inverse association between HMB levels and frailty status. These findings support the design of targeted clinical trials to evaluate the effect of HMB supplementation in older frail people with low HMB levels.

Project description:Malnutrition may result in abnormal biochemical and hematological indices. This planned prespecified analysis investigated the effects of a specialized oral nutritional supplement (ONS) on biochemical and hematological indices in community-dwelling older adults at risk of malnutrition. In the Strengthening Health in ELDerly through nutrition (SHIELD) study, 811 older adults aged 65 years and above took part in this randomized, double-blind, placebo-controlled, multi-center study. Participants were randomly allocated to either a complete and balanced specialized ONS (each serving provides 262 kcal, 10.5 g protein, 7.75 µg vitamin D3, and 0.74 g calcium β-hydroxy-β-methylbutyrate) and dietary counselling (intervention group) or a placebo and dietary counselling (placebo group). Both groups consumed study products twice a day for 180 days. Data were collected at baseline, day 90, and day 180. Blood analysis results at follow-up visits were analyzed using repeated measures analysis of covariance with adjustments for confounders. Overall, when compared with the placebo group, the intervention group showed significantly greater urea (6.0 mmol/L vs. 5.4 mmol/L, p < 0.001), urea to creatinine ratio (4.39 vs. 4.26, p < 0.001), prealbumin (24.9 mg/dL vs. 24.0 mg/dL, p < 0.001), vitamin B12 (480.0 pmol/L vs. 420.1 pmol/L, p < 0.001), and globulin levels (26.8 g/L vs. 26.5 g/L, p = 0.032). The intervention group also had a significantly higher absolute reticulocyte count (62.0 × 103/µL vs. 58.2 × 103/µL, overall p < 0.001) and mean platelet volume (10.0 fL vs. 9.9 fL, overall p = 0.003). Furthermore, significant improvements were seen in total protein at day 90 (71.7 g/L vs. 71.1 g/L, p = 0.017) and in absolute monocyte count at day 90 (0.50 × 103/µL vs. 0.47 × 103/µL, p = 0.009) in the intervention group. In conclusion, daily consumption of a specialized ONS for six months led to significant improvements in biochemical and hematological indices in community-dwelling older adults at risk of malnutrition.

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Muscle-building supplement β-hydroxy β-methylbutyrate stimulates the maturation of oligodendroglial progenitor cells to oligodendrocytes.

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Muscle-building supplement β-hydroxy β-methylbutyrate stimulates the maturation of oligodendroglial progenitor cells to oligodendrocytes.

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