Drugs that affect the myostatin-activin pathway
The first in-human study investigating ACE-083 (a locally acting follistatin-based therapeutic that binds myostatin and other muscle regulators) in healthy postmenopausal women showed peak volume increases of 14.5% and 8.9% in the rectus femoris and tibialis anterior muscles (compared with placebo), respectively, but without changes in strength.[86]Glasser CE, Gartner MR, Wilson D, et al. Locally acting ACE-083 increases muscle volume in healthy volunteers. Muscle Nerve. 2018 Jun;57(6):921-6.
https://onlinelibrary.wiley.com/doi/10.1002/mus.26113
http://www.ncbi.nlm.nih.gov/pubmed/29486514?tool=bestpractice.com
Subsequently, two clinical trials reported significant changes in various components of body composition, with a very mild effect on muscle function and strength, with LY2495655 (a monoclonal antibody that binds and neutralizes myostatin) and bimagrumab (a monoclonal antibody that binds to and inhibits activin receptor type 2B).[87]Becker C, Lord SR, Studenski SA, et al; STEADY Group. Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial. Lancet Diabetes Endocrinol. 2015 Dec;3(12):948-57.
http://www.ncbi.nlm.nih.gov/pubmed/26516121?tool=bestpractice.com
[88]Rooks D, Praestgaard J, Hariry S, et al. Treatment of sarcopenia with bimagrumab: results from a phase II, randomized, controlled, proof-of-concept study. J Am Geriatr Soc. 2017 Sep;65(9):1988-95.
http://www.ncbi.nlm.nih.gov/pubmed/28653345?tool=bestpractice.com
These drugs are still considered investigational, and further research is required.
Omega-3 fatty acids
Omega-3 fatty acids have the potential to enhance skeletal muscle anabolism and may reduce the impact of periods of limb immobilization on muscle mass atrophy.[89]McGlory C, Calder PC, Nunes EA. The influence of omega-3 fatty acids on skeletal muscle protein turnover in health, disuse, and disease. Front Nutr. 2019 Sep 6;6:144.
https://www.frontiersin.org/articles/10.3389/fnut.2019.00144/full
http://www.ncbi.nlm.nih.gov/pubmed/31555658?tool=bestpractice.com
Leucine and hydroxymethylbutyrate (HMB)
Leucine, an essential amino acid, has the potential to activate the anabolic pathway leading to protein synthesis.[90]De Bandt JP. Leucine and mammalian target of rapamycin-dependent activation of muscle protein synthesis in aging. J Nutr. 2016 Dec;146(12):2616S-624S.
https://www.sciencedirect.com/science/article/pii/S0022316623008155
http://www.ncbi.nlm.nih.gov/pubmed/27934653?tool=bestpractice.com
It has been suggested that supplementation of leucine can enhance and promote higher muscle mass and improve functional capacity in the long term.[91]Martínez-Arnau FM, Fonfría-Vivas R, Cauli O. Beneficial effects of leucine supplementation on criteria for sarcopenia: a systematic review. Nutrients. 2019 Oct 17;11(10):2504.
https://www.mdpi.com/2072-6643/11/10/2504
http://www.ncbi.nlm.nih.gov/pubmed/31627427?tool=bestpractice.com
HMB is a metabolite of the oxidation of leucine; around 5% of ingested leucine is converted to HMB.[92]Van Koevering M, Nissen S. Oxidation of leucine and alpha-ketoisocaproate to beta-hydroxy-beta-methylbutyrate in vivo. Am J Physiol. 1992 Jan;262(1 Pt 1):E27-31.
http://www.ncbi.nlm.nih.gov/pubmed/1733247?tool=bestpractice.com
HMB plays a role in preserving muscle mass through slowing muscle protein breakdown.[93]Smith HJ, Wyke SM, Tisdale MJ. Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by beta-hydroxy-beta-methylbutyrate. Cancer Res. 2004 Dec 1;64(23):8731-5.
https://aacrjournals.org/cancerres/article/64/23/8731/512101/Mechanism-of-the-Attenuation-of-Proteolysis
http://www.ncbi.nlm.nih.gov/pubmed/15574784?tool=bestpractice.com
A study of young resistance-trained athletes receiving HMB for 12 weeks showed comparable effects to leucine supplementation on muscle hypertrophy.[94]Jakubowski JS, Wong EPT, Nunes EA, et al. Equivalent hypertrophy and strength gains in beta-hydroxy-beta-methylbutyrate- or leucine-supplemented men. Med Sci Sports Exerc. 2019 Jan;51(1):65-74.
https://journals.lww.com/acsm-msse/fulltext/2019/01000/equivalent_hypertrophy_and_strength_gains_in.10.aspx
http://www.ncbi.nlm.nih.gov/pubmed/30113522?tool=bestpractice.com
An open-label randomized controlled trial in healthy older women concluded that HMB showed promising results in strength, although it had no significant effects on Short Physical Performance Battery score.[95]Berton L, Bano G, Carraro S, et al. Effect of oral beta-hydroxy-beta-methylbutyrate (HMB) supplementation on physical performance in healthy old women over 65 years: an open label randomized controlled trial. PLoS One. 2015 Nov 3;10(11):e0141757.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141757
http://www.ncbi.nlm.nih.gov/pubmed/26529601?tool=bestpractice.com
However, the role of HMB in older adults is still under debate.[96]Courel-Ibáñez J, Vetrovsky T, Dadova K, et al. Health benefits of beta-hydroxy-beta-methylbutyrate (HMB) supplementation in addition to physical exercise in older adults: a systematic review with meta-analysis. Nutrients. 2019 Sep 3;11(9):2082.
https://www.mdpi.com/2072-6643/11/9/2082
http://www.ncbi.nlm.nih.gov/pubmed/31484462?tool=bestpractice.com
The task force of the International Conference on Sarcopenia and Frailty Research (ICSFR) considered the benefits of supplementation with leucine and HMB in the management of sarcopenia, but it found the evidence base to be very limited for older adults with sarcopenia and was uncertain that any effect could be established.[2]Dent E, Morley JE, Cruz-Jentoft AJ, et al. International clinical practice guidelines for sarcopenia (ICFSR): screening, diagnosis and management. J Nutr Health Aging. 2018;22(10):1148-61.
http://www.ncbi.nlm.nih.gov/pubmed/30498820?tool=bestpractice.com