Mechanism of the Attenuation of Proteolysis-Inducing Factor Stimulated Protein Degradation in Muscle by β-Hydroxy-β-Methylbutyrate

Abstract

The leucine metabolite ␤-hydroxy-␤-methylbutyrate (HMB) prevents muscle protein degradation in cancer-induced weight loss through attenuation of the ubiquitin-proteasome proteolytic pathway. To investigate the mechanism of this effect, the action of HMB on protein breakdown and intracellular signaling leading to increased proteasome expression by the tumor factor proteolysis-inducing factor (PIF) has been studied in vitro using murine myotubes as a surrogate model of skeletal muscle. A comparison has been made of the effects of HMB and those of eicosapentaenoic acid (EPA), a known inhibitor of PIF signaling. At a concentration of 50 mol/L, EPA and HMB completely attenuated PIF-induced protein degradation and induction of the ubiquitin-proteasome proteolytic pathway, as determined by the "chymotrypsin-like" enzyme activity, as well as protein expression of 20S proteasome ␣-and ␤-subunits and subunit p42 of the 19S regulator. The primary event in PIF-induced protein degradation is thought to be release of arachidonic acid from membrane phospholipids, and this process was attenuated by EPA, but not HMB, suggesting that HMB might act at another step in the PIF signaling pathway. EPA and HMB at a concentration of 50 mol/L attenuated PIF-induced activation of protein kinase C and the subsequent degradation of inhibitor B␣ and nuclear accumulation of nuclear factor B. EPA and HMB also attenuated phosphorylation of p42/44 mitogen-activated protein kinase by PIF, thought to be important in PIF-induced proteasome expression. These results suggest that HMB attenuates PIF-induced activation and increased gene expression of the ubiquitin-proteasome proteolytic pathway, reducing protein degradation.

β-Hydroxy-β-Methylbutyrate Did Not Enhance High Intensity Resistance Training-Induced Improvements in Myofiber Dimensions and Myogenic Capacity in Aged Female Rats

“…As expected, protein synthesis decreased significantly by 30-50% in the presence of all three catabolic agents; however, HMB treatment effectively abolished these reductions. There is also evidence that HMB can attenuate the increase in proteasome activity generated by proteolysis-inducing factor, a tumor-specific product implicated in the development of cancer cachexia (Smith et al, 2004). Moreover, Kornasio and colleagues (2009) reported that myoblasts incubated with HMB showed increased cell number, MyoD and myogenin expression, and myosin heavy chain content compared to untreated conditions.…”

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

“…The significance of the convergence of these signaling pathways on NF-κB in cancerrelated muscle atrophy has been shown experimentally in a number of different ways. Both genetic or pharmacologic inhibition of NF-κB prevents muscle mass loss, improves strength, and increases muscle regeneration [2,9,16,28,31,36,46,48,57,70,75]. These numerous studies implicate NF-κB as having much potential as a therapeutic target in cancer-induced muscle loss.…”

Competitive Edge: Review of the Role of Glutamine, Arginine and β -Hydroxy- β -Methylbutyrate Supplements for Enhancing Athletic Performance in Addition to Benefiting the Body During Times of Stress, Illness and Wound Healing

“…HMB (β-hydroxy-β-mehtylbutyrate) is a normal constituent of muscle that has been hypothesized to protect muscle from stress-related damage, to build lean body mass (LBM) and to decrease muscle breakdown [15]. Studies from 2004 and 2005 demonstrate the role of HMB in preventing muscle loss in cancer patients [16,17].…”

“…In 2004, Smith et al [16,17] studied how HMB may reduce the inflammatory response by down-regulating the action of proteolysis-inducing factor (PIF), normalize metabolism and help prevent muscle breakdown in cancerrelated weight loss. The action of HMB on protein breakdown and intracellular signaling leading to increased proteasome expression by the tumor factor proteolysis-inducing factor (PIF) was studied in vitro using murine myotubes as a surrogate model of skeletal muscle.…”

“…The action of HMB on protein breakdown and intracellular signaling leading to increased proteasome expression by the tumor factor proteolysis-inducing factor (PIF) was studied in vitro using murine myotubes as a surrogate model of skeletal muscle. Results suggest that HMB attenuates PIF-induced activation and increased gene expression of the ubiquitin-proteasome proteolytic pathway, reducing protein degradation [16]. In 2005, Smith et al [17] further studied the attenuation of proteasome expression reflected as a reduction in protein degradation in gastrocnemius muscle of cachectic mice treated with HMB.…”