HMB is used in several nutritional supplement shakes and formulas such as Ensure® aimed at decreasing muscle loss. HMB’s mechanism of action may be linked to its effect on inflammatory pathways. An increase in the ubiquitin-proteosome pathway stimulates muscle degradation that is unresponsive to nutritional interventions, and thus, must be addressed through supplementation of compounds that can directly slow the pathway. Increased NF-κβ is believed to stimulate the ubiquitin-proteosome pathway. There is also evidence that increased cytokines – especially TNF-α and IL-6 – stimulates the pathway and leads to muscle degradation(1).

HMB’s ability to down-regulate NF-κβ activation indicate a mechanistic rationale behind its ability to reduce muscle wasting. HMB has also been shown to reduce TNF-α, another cytokine indicated in ubiquitin-proteosome pathway muscle wasting. By down-regulating these factors, we can see that HMB supplementation reduces byproducts of muscle cell breaking, especially creatine kinase and lactate dehydrogenase – two enzymes found at high levels in muscle cells and during times of muscle damage, at high levels in the blood.

MSM’s effects on both NF-κβ and TNF-α are similar to those of HMB. The downstream byproducts of creatine kinase and lactate dehydrogenase seem similar as well.


One study of HMB on tumor-induced rats showed a 17% decrease in NF-κβ activation(2). A study of the effects of MSM on murine macrophages showed a decrease in NF-κβ, although it was not quantified(3). Although one study was live rats and the other in vitro, both stimulated inflammation of some form. The HMB study used tumors and the MSM study used lipopolysaccharides. In a study on human chondrocyte cells, MSM was shown to reduce the NF-κβ activation by 30%(4).


Two studies have assessed HMB’s effect on TNF-α. A post exercise study found that HMB likely decreased TNF-α levels immediately after exercise compared to placebo, but the results were not conclusive(5). An in vitro study on mononuclear cells found that HMB significantly reduced the levels of TNF-α(6). In an in vitro study on human chondrocyte cells, MSM was found to reduce the mRNA expression of TNF-α by 30%(7). An in vitro study using LPS induced murine macrophages showed that MSM at 10μg/mL significantly reduced TNF-α levels(3). And two animal studies showed that MSM reduced the levels of TNF-α in rats and mice with chemically-induced liver injuries – paraquat and carbon tetrachloride being the liver-damaging chemicals(8,9).

Creatine Kinase and Lactate Dehydrogenase

These two outcomes of muscle damage are the result of muscle cells breaking and dying. A possible reason for this damage is through inflammation – high levels of TNF-α and NF-κβ are possible culprits. Research shows the similarity between HMB and MSM. A study on HMB by and an MSM study set out similar parameters and collected similar outcomes(Barmaki et al.,2012; Knitter et al., 2013). The table below shows them side by side.



These two studies have similar exercise interventions and outcome measures. If you look specifically at the 24 hr (1day) and 48hr (2day) data points they look very similar between the two groups. These are about as similar to results as you’re likely to see between two different supplements. It would be just as likely to see this much variation in results between two studies of the same intervention. This study indicates that HMB and MSM may have similar inflammatory properties, resulting in similar downstream results.

Benefits of MSM

Although in the manner described above, HMB and MSM share very similar properties. Some differences between the two though are important and noteworthy.

IL-1, IL-6, IL-8

Several studies indicate that MSM reduces the levels of IL-1, an acute inflammatory cytokine. Three studies – two in vitro human studies and one animal study – have shown MSM significantly reducing the IL-1(Amirshahrokhi et al., 2011; Kloesch et al., 2011; Oshima et al., 2007). There are also three studies – one in vitro and two animal studies – indicating that MSM reduces the levels of IL-6(3,4,9). IL-1 and IL-6 are important acute cytokines often associated with TNF-α. IL-6, along with TNF-α, have both been suggested to be responsible for protein degradation. A study on human chondrocytes shows that MSM reduces the levels of IL-8(4), a chemokine responsible for mobilizing neutrophils. Mobilized neutrophils are suspected in causing muscle damage hours after exercise. Two HMB studies showed no improvement in IL-6 levels, one of which also showed no improvements in IL-1(Kuhls et al., 2007; Zadik et al. , 2009).

Oxidative Stress

Oxidative stress is a major contributing factor in muscle damage, especially in the elderly. MSM has repeatedly shown anti-oxidative properties – in vitro studies, animal studies, and human exercise studies( Amirshahrokhi et al., 2013; Barmaki et al., 2012; Mohammadi et al., 2012; Nakhostin-Roohi et al., 2011). There is little to no information on the anti-oxidative properties of HMB. Especially in the elderly, reducing oxidative stress is paramount in reducing muscle loss.

Pain and Exercise

Most studies on the elderly digesting HMB are conducted without an exercise intervention. In the one study that combined HMB with exercise, no differences were found between HMB and placebo(Vukovich et al., 2001). Indicating that for the elderly, exercise is as beneficial as HMB in maintaining muscle. A common barrier to exercise in the elderly is muscle and joint pain. Several studies have shown MSM to be effective in alleviating joint pain, and another study indicates that MSM is effective in relieving muscle pain hours after exercise(3,18,19).

Take Aways

It is likely that HMB’s primary mechanism of action in reducing muscle loss centers around its effects on the ubiquitin-proteosome pathway through NF-κβ and TNF-α reduction. This leads to less muscle cell damage and helps maintain muscle mass. MSM has similar effects on NF-κβ and TNF-α, and the downstream outcomes produced by these effects, creatine kinase, and lactate dehydrogenase, are very similar to those of HMB. Where MSM is of added benefit, is its effects on IL-1, IL-6, and IL-8 to reduce acute inflammation, its anti-oxidative properties, and its ability to reduce both joint and muscle pain.

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