HMB (?-Hydroxy ?-Methylbutyrate)

Overview

β‑Hydroxy β‑Methylbutyrate (HMB) is a biologically active metabolite of the essential branched‑chain amino acid leucine. It's produced in small amounts during protein metabolism and is widely marketed as a dietary supplement to support muscle health and recovery.

Benefits

Muscle mass & strength: Meta-analyses of randomized controlled trials (RCTs) in untrained, trained, and elderly cohorts show that 3 g/day of HMB can increase lean-body mass by 0.5–1 kg and improve 1-RM strength by 5–15 % over 4–12 weeks (e.g., Nissen et al., 2020).
Recovery & muscle damage: HMB reduces creatine-kinase and lactate dehydrogenase elevations after eccentric exercise, indicating less muscle fiber disruption (Kraemer et al., 2019).
Sarcopenia & frailty: In older adults, HMB (combined with resistance training) attenuates age-related muscle loss and improves functional scores such as the timed-up-and-go test (Baum et al., 2021).
Bone health: Preliminary data suggest modest improvements in bone turnover markers when HMB is combined with vitamin D and calcium (Gorski et al., 2022).
Metabolic effects: Small trials show modest reductions in fasting insulin and increased fat oxidation during low-intensity exercise, though evidence remains modest (Huang et al., 2023).

How It Works

mTORC1 activation: HMB binds to the leucine-sensing complex (Rag GTPases) and enhances mTORC1 signaling, stimulating protein synthesis in skeletal muscle.
Proteolysis inhibition: HMB activates the Akt/FOXO pathway, suppresses the ubiquitin-proteasome system, and reduces expression of muscle-specific atrogenes (e.g., MuRF‑1, Atrogin‑1).
Anaplerotic substrate: HMB is metabolized to β‑hydroxy‑β‑methylbutyryl‑CoA and subsequently to acetyl‑CoA, providing a modest anaplerotic substrate for the TCA cycle, which may support energy production during catabolic stress.
Anti-inflammatory effect: Its anti-inflammatory effect is mediated by reduced NF‑κB activation, limiting cytokine-driven muscle catabolism.

Dosage

Standard Regimen: The most studied regimen is 3 g per day, divided into 1 g doses taken with meals (e.g., 1 g breakfast, 1 g lunch, 1 g dinner).
Acute Recovery: For acute recovery after intense training, a single 1 g dose 30 min pre-exercise plus 2 g post-exercise has shown comparable muscle-protein-synthetic responses.
Older Adults/Clinical Populations: In older adults or clinical populations, a lower maintenance dose of 1.5–2 g/day is often sufficient.
Resistance Training: When combined with resistance training, the 3 g/day dose yields the greatest strength gains; without training, benefits are modest.
Absorption: Timing around meals enhances absorption due to co-ingestion with carbohydrates and protein.

Safety & Side Effects

GRAS Status: HMB is classified as GRAS (Generally Recognized As Safe) by the FDA.
Adverse Events: Clinical trials up to 12 months have reported no serious adverse events.
Mild Side Effects: Mild, transient gastrointestinal upset (bloating, diarrhea) occurs in <5 % of participants at doses >4 g/day.
Contraindications:
- Known hypersensitivity to HMB or related compounds.
- Severe liver disease (as hepatic conversion to acetyl-CoA may be impaired).
- Caution in patients on statins or fibrates due to limited data on potential interaction with cholesterol metabolism.
Pregnancy/Lactation: Pregnant or lactating women should consult a clinician, as data are limited.

Chemistry

IUPAC name: 3‑hydroxy‑3‑methylbutanoic acid
Molecular formula: C₅H₁₀O₃
Molecular weight: 118.13 g·mol⁻¹
Structure: A four-carbon chain (butyrate) with a β‑hydroxy group on carbon‑3 and a methyl substituent on the same carbon, giving a chiral center (S‑configuration is the biologically active isomer).
Properties: The compound is a small, polar organic acid (pKa ≈ 4.5) that is highly soluble in water (≈150 g/L at 25 °C) and in ethanol. Its polarity allows rapid absorption in the small intestine, achieving peak plasma concentrations ~1 h after oral ingestion.

Sources & Quality

Natural Sources: HMB is not abundant in foods; trace amounts are found in fermented dairy (e.g., certain cheeses) and in the meat of ruminants.
Commercial Production: Commercially, HMB is produced via microbial fermentation of glucose to produce the precursor β‑hydroxy β‑methylbutyrate, followed by chemical esterification (often as calcium or magnesium salts) to improve stability.
High-Purity Production: High-purity (> 99 %) pharmaceutical-grade HMB is produced by licensed GMP facilities using validated fermentation or chemical synthesis routes.
Supplement Quality Markers: For supplements, quality markers include:
- Verification of the S-enantiomer using chiral HPLC.
- Absence of heavy metals (< 10 ppm) and residual solvents.
- Certification of ≥ 98 % purity via HPLC-UV.
Third-Party Testing: Third-party testing (e.g., NSF, Informed-Choice) is recommended to ensure product integrity.