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β-Hydroxy-β-methylbutyrate, mitochondrial biogenesis, and skeletal muscle health

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Abstract

The metabolic roles of mitochondria go far beyond serving exclusively as the major producer of ATP in tissues and cells. Evidence has shown that mitochondria may function as a key regulator of skeletal muscle fiber types and overall well-being. Maintaining skeletal muscle mitochondrial content and function is important for sustaining health throughout the lifespan. Of great importance, β-hydroxy-β-methylbutyrate (HMB, a metabolite of l-leucine) has been proposed to enhance the protein deposition and efficiency of mitochondrial biogenesis in skeletal muscle, as well as muscle strength in both exercise and clinical settings. Specifically, dietary supplementation with HMB increases the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), which represents an upstream inducer of genes of mitochondrial metabolism, coordinates the expression of both nuclear- and mitochondrion-encoded genes in mitochondrial biogenesis. Additionally, PGC-1α plays a key role in the transformation of skeletal muscle fiber type, leading to a shift toward type I muscle fibers that are rich in mitochondria and have a high capacity for oxidative metabolism. As a nitrogen-free metabolite, HMB holds great promise to improve skeletal muscle mass and function, as well as whole-body health and well-being of animals and humans.

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Abbreviations

AMPK:

AMP-activated protein kinase

BCAA:

Branched-chain amino acid(s)

BCAAem:

Branched-chain amino acid-enriched mixture

CaMK:

Calmodulin-dependent protein kinase

CaMKKβ:

Ca2+-activated kinase calmodulin-dependent kinase kinase-β

EDL:

Extensor digitorum longus

ERRα:

Estrogen-related receptor α

HMB:

β-Hydroxy-β-methylbutyrate

LBM:

Lean body mass

LKB1:

Liver kinase B1

Mef2:

Myocyte enhancer factor 2

MHC:

Myosin heavy chain

OXPHOS:

Oxidative phosphorylation

PGC-1α:

Peroxisome proliferator-activated receptor gamma co-activator 1-alpha

PPARα:

Peroxisome proliferator-activated receptor α

ROS:

Reactive oxygen species

SIRT1:

Silent information regulator transcript 1

TFAM:

Mitochondrial transcription factor A

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Acknowledgments

This study was jointly supported by the National Natural Science Foundation of China (31330075;31110103909, 31572416, and 31372319), Special Fund for Agro-scientific Research in the Public Interest (201403047), Innovation Research Team Development Program of MOE of China (IRT0945), The Chinese Academy of Science STS Project (KFJ-EW-STS-063), Key Projects in the National Science and Technology Pillar Program (2013BAD21B04), Hunan Key Project (2015NK1002), Changsha Lvye Biotechnology Limited Company Academician Expert Workstation, Guangdong Wangda Group Academician Workstation for Clean Feed Technology Research and Development in Swine, Guangdong Hinapharm Group Academician Workstation for Biological Feed and Feed Additives and Animal Intestinal Health, Hunan New Wellful Co. Ltd, Academician Workstation, Hubei Provincial Key Project for Scientific and Technical Innovation (2014ABA022), Hubei Hundred Talent program, and the Natural Science Foundation of Hubei Province (2013CFA097, 2013CFB325, 2012FFB04805, and 2011CDA131).

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    Authors and Affiliations

    1. College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, China

      Xi He, Kang Yao & Yulong Yin

    2. Hunan Co-Innovation Center of Animal Production Safety, Changsha, 410128, China

      Xi He

    3. Scientific Observation and Experiment Station of Animal Nutrition and Feed Science in South-Central China, Ministry of Agriculture, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, No. 644 Yuanda Road, Furong District, Changsha, 410125, Hunan, China

      Yehui Duan, Kang Yao, Fengna Li, Guoyao Wu & Yulong Yin

    4. University of Chinese Academy of Sciences, Beijing, 100039, China

      Yehui Duan

    5. Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, China

      Yongqing Hou, Guoyao Wu & Yulong Yin

    6. Department of Animal Science, Texas A&M University, College Station, TX, 77843, USA

      Guoyao Wu

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    1. Xi He
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    Correspondence to Kang Yao or Yulong Yin.

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    X. He and Y. Duan contributed equally to this study.

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    He, X., Duan, Y., Yao, K. et al. β-Hydroxy-β-methylbutyrate, mitochondrial biogenesis, and skeletal muscle health. Amino Acids 48, 653–664 (2016). https://doi.org/10.1007/s00726-015-2126-7

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