In Aging Cell, researchers have published a paper on a cellular energy source that appears to be a key signaling molecule in sarcopenia.
A little-explored molecule
Sarcopenia, a condition that increases with aging, reduces muscle mass in older people, and leads to a decreased quality of life [1], has been documented to have multiple root causes. Among them are signaling pathways, whose dysregulation affects the number and function of energy-producing mitochondria [2]. There are no approved treatments that directly affect these pathways.
Much research has focused on overall approaches that have been documented to positively affect sarcopenia, such as caloric restriction [3] and other metabolic interventions [4]. In particular, some research has found that a diet that induces ketosis is beneficial in combating muscle loss [5] and causes an increase in β-hydroxybutyrate (β-HB), as does exercise [6].
However, despite its association with interventions that reduce sarcopenia, β-HB itself has been little studied in this respect. These researchers hypothesized that this particular ketone body, which is both a signaling molecule and an alternative energy source [7], is potentially effective as a treatment for sarcopenia.
A key enzyme and a key pathway
To test their hypothesis, the researchers first investigated genetically diverse mice. The natural synthesis of β-HB is governed by an enzyme, HMGCS2, and more HMGCS2 leads to more β-HB. The size of the gastrocnemius, a major leg muscle, was correlated with HMGCS2 mRNA in these mice, as were the mRNA levels of two related enzymes. All three of these enzymes were found to decrease with aging in these mice. These findings were confirmed in primates, and trends towards these findings were found in human data.
The researchers then studied the mouse myoblast cell line C2C12, which is commonly used as a model of sarcopenia. Myosin heavy chain, a crucial protein for muscle use, is decreased with the administration of TNF-α, an inflammatory cytokine that increases with aging. Administering β-HB counteracted this effect, and it did not seem to affect cells that had not been exposed to TNF-α.
These encouraging results led to further experiments with mice. 23-month-old mice, near the end of their lifespan, were given either β-HB or a control for one month. The mice that received β-HB were able to run for longer, had larger muscles, and trended towards having more grip strength than the control group. They also had increased myoglobin, a protein required for muscle function.
Such findings were also replicated in C. elegans, a common worm model of aging. Worms tend to bend and move less with aging, but administering sufficient β-HB to older worms restored their function and encouraged the maintenance of muscle fibers. Increasing the worms’ production of β-HB through the worm analog of HMGCS2 yielded similar benefits.
A gene expression analysis found that cells given β-HB had more functional mitochondria in multiple respects, including additional energy production, better organization, and better use of oxygen. These findings were corroborated with a pathway analysis, which found similar upregulation in similar areas. Specifically, histone Kbhb was found to be crucial in the effects of β-HB, as blocking this histone nullified its positive effects. This same histone is upregulated in caloric restriction.
These findings open up an entirely new line of inquiry for drug discovery and potential treatments. While off-target effects and potential dangers have yet to be discovered, if aging muscle cells can be encouraged to produce more β-HB or histone Kbhb, it may be possible to significantly attenuate the frailty that comes with this crippling and dangerous disorder.
Literature
[1] ESPINOZA, B. S. M., RODRIGUEZ, A. S., CARRASCO, O. R., ROBLEDO, L. M. F. G., & FUNES, J. A. A. (2021). Sarcopenia Is Associated With Physical and Mental Components of Health-Related Quality of Life in Older Adults.
[2] Yin, L., Li, N., Jia, W., Wang, N., Liang, M., Yang, X., & Du, G. (2021). Skeletal muscle atrophy: From mechanisms to treatments. Pharmacological research, 172, 105807.
[3] Jang, Y. C., Liu, Y., Hayworth, C. R., Bhattacharya, A., Lustgarten, M. S., Muller, F. L., … & Van Remmen, H. (2012). Dietary restriction attenuates age‐associated muscle atrophy by lowering oxidative stress in mice even in complete absence of CuZnSOD. Aging cell, 11(5), 770-782.
[4] Hamrick, M. W., & Stranahan, A. M. (2020). Metabolic regulation of aging and age-related disease. Ageing research reviews, 64, 101175.
[5] Wallace, M. A., Aguirre, N. W., Marcotte, G. R., Marshall, A. G., Baehr, L. M., Hughes, D. C., … & Baar, K. (2021). The ketogenic diet preserves skeletal muscle with aging in mice. Aging cell, 20(4), e13322.
[6] Evans, M., Cogan, K. E., & Egan, B. (2017). Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. The Journal of physiology, 595(9), 2857-2871.
[7] Puchalska, P., & Crawford, P. A. (2017). Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell metabolism, 25(2), 262-284.
