The Endocrine Actions of Undercarboxylated Osteocalcin in Skeletal Muscle: Effects and Mechanisms

  • Xuzhu Lin
  • Alan Hayes
  • Glenn McConell
  • Gustavo Duque
  • Tara C. Brennan-Speranza
  • Itamar LevingerEmail author


Recent evidence has indicated that bone interacts with skeletal muscle, in part, via undercarboxylated osteocalcin (ucOC) − a hormone predominantly secreted from osteoblasts. Experimental studies suggest ucOC has both metabolic and anabolic effects on muscle cells. These effects include improved muscle insulin sensitivity, glucose and fatty acid uptake, mitochondrial function, protein synthesis, as well as myoblast proliferation and differentiation. Current mechanistic evidence also implicates that the underlying mechanisms by which ucOC affects muscle cells include multiple signaling pathways which are orchestrated by its putative receptor − G protein-coupled receptor, class C, group 6, member A (GPRC6A). The ucOC/GPRC6A axis may trigger the activation of signaling cascades involving protein kinase B (Akt), extracellular signal-regulated kinases (ERK), 5′ adenosine monophosphate-activated protein kinase (AMPK), and numerous alternative pathways. The identification of the endocrine actions of ucOC in muscle indicates a potential therapeutic avenue for the treatment of muscle insulin resistance and muscle atrophy. However, it is still unknow whether the roles ascribed to ucOC in rodent models translate to humans, as the majority of current studies are performed in cell culture and animal models, while the evidence in humans is relatively scant. Therefore, further research is warranted to clarify similar beneficial effects of ucOC on human skeletal muscle.


Osteocalcin Undercarboxylated osteocalcin Osteoblasts Fatty acids Mitochondria G protein-coupled receptor Insulin Animal models Muscle-bone crosstalk 


  1. Alers S, Löffler AS, Wesselborg S, Stork B (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32(1):2–11PubMedPubMedCentralCrossRefGoogle Scholar
  2. Alvim RO, Cheuhen MR, Machado SR, Sousa AGP, Santos PC (2015) General aspects of muscle glucose uptake. An Acad Bras Cienc 87(1):351–368PubMedPubMedCentralCrossRefGoogle Scholar
  3. Arias EB, Kim J, Funai K, Cartee GD (2007) Prior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle. Am J Physiol Endocrinol Metab 292(4):E1191–EE200PubMedCrossRefGoogle Scholar
  4. Ayala JE, Bracy DP, James FD, Julien BM, Wasserman DH, Drucker DJ (2008) The glucagon-like peptide-1 receptor regulates endogenous glucose production and muscle glucose uptake independent of its incretin action. Endocrinology 150(3):1155–1164PubMedPubMedCentralCrossRefGoogle Scholar
  5. Ben-Sahra I, Manning BD (2017) mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol 45:72–82PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bilodeau PA, Coyne ES, Wing SS (2016) The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation. Am J Phys Cell Phys 311(3):C392–C403CrossRefGoogle Scholar
  7. Björnholm M, Zierath J (2005) Insulin signal transduction in human skeletal muscle: identifying the defects in type II diabetes. Biochem Soc Trans 33(2):354–357PubMedCrossRefGoogle Scholar
  8. Bonaldo P, Sandri M (2013) Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech 6(1):25–39PubMedPubMedCentralCrossRefGoogle Scholar
  9. Brennan-Speranza TC, Henneicke H, Gasparini SJ et al (2012) Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J Clin Invest 122(11):4172PubMedPubMedCentralCrossRefGoogle Scholar
  10. Brooks NE, Myburgh KH (2014) Skeletal muscle wasting with disuse atrophy is multi-dimensional: the response and interaction of myonuclei, satellite cells and signaling pathways. Front Physiol 5:99PubMedPubMedCentralCrossRefGoogle Scholar
  11. Brotto M, Johnson ML (2014) Endocrine crosstalk between muscle and bone. Curr Osteoporos Rep 12(2):135–141PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bruce CR, Mertz VA, Heigenhauser GJ, Dyck DJ (2005) The stimulatory effect of globular adiponectin on insulin-stimulated glucose uptake and fatty acid oxidation is impaired in skeletal muscle from obese subjects. Diabetes 54(11):3154–3160PubMedCrossRefGoogle Scholar
  13. Cannavino J, Brocca L, Sandri M, Grassi B, Bottinelli R, Pellegrino MA (2015) The role of alterations in mitochondrial dynamics and PGC-1α over-expression in fast muscle atrophy following hindlimb unloading. J Physiol 593(8):1981–1995PubMedPubMedCentralCrossRefGoogle Scholar
  14. Cartee GD (2015) Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise. Am J Physiol Endocrinol Metab 309(12):E949–EE59PubMedPubMedCentralCrossRefGoogle Scholar
  15. Cartee GD, Funai K (2009) Exercise and insulin: convergence or divergence at AS160 and TBC1D1? Exerc Sport Sci Rev 37(4):188PubMedPubMedCentralCrossRefGoogle Scholar
  16. Cartee GD, Young DA, Sleeper MD, Zierath J, Wallberg-Henriksson H, Holloszy J (1989) Prolonged increase in insulin-stimulated glucose transport in muscle after exercise. Am J Physiol Endocrinol Metab 256(4):E494–E4E9CrossRefGoogle Scholar
  17. Chambers MA, Moylan JS, Smith JD, Goodyear LJ, Reid MB (2009) Stretch-stimulated glucose uptake in skeletal muscle is mediated by reactive oxygen species and p38 MAP-kinase. J Physiol 587(13):3363–3373PubMedPubMedCentralCrossRefGoogle Scholar
  18. Charette S, McEvoy L, Pyka G et al (1991) Muscle hypertrophy response to resistance training in older women. J Appl Physiol 70(5):1912–1916PubMedCrossRefGoogle Scholar
  19. Chen HC, Bandyopadhyay G, Sajan MP, Kanoh Y, Standaert M, Farese RV (2002) Activation of the ERK pathway and atypical protein kinase C isoforms in exercise-and aminoimidazole-4-carboxamide-1-β-d-riboside (AICAR)-stimulated glucose transport. J Biol Chem 277(26):23554–23562PubMedCrossRefGoogle Scholar
  20. DeFronzo R, Jacot E, Jequier E, Maeder E, Wahren J, Felber J (1981) The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30(12):1000–1007PubMedPubMedCentralCrossRefGoogle Scholar
  21. Demling RH (2009) Nutrition, anabolism, and the wound healing process: an overview. Eplasty 9:e9PubMedPubMedCentralGoogle Scholar
  22. Deng J-Y, Hsieh P-S, Huang J-P, Lu L-S, Hung L-M (2008) Activation of estrogen receptor is crucial for resveratrol-stimulating muscular glucose uptake via both insulin-dependent and-independent pathways. Diabetes 57(7):1814–1823PubMedPubMedCentralCrossRefGoogle Scholar
  23. Devlin J, Horton E (1985) Effects of prior high-intensity exercise on glucose metabolism in normal and insulin-resistant men. Diabetes 34(10):973–979PubMedCrossRefGoogle Scholar
  24. Fanzani A, Conraads VM, Penna F, Martinet W (2012) Molecular and cellular mechanisms of skeletal muscle atrophy: an update. J Cachexia Sarcopenia Muscle 3(3):163–179PubMedPubMedCentralCrossRefGoogle Scholar
  25. Ferron M, Hinoi E, Karsenty G, Ducy P (2008) Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A 105(13):5266–5270PubMedPubMedCentralCrossRefGoogle Scholar
  26. Ferron M, Wei J, Yoshizawa T, Ducy P, Karsenty G (2010) An ELISA-based method to quantify osteocalcin carboxylation in mice. Biochem Biophys Res Commun 397(4):691–696PubMedPubMedCentralCrossRefGoogle Scholar
  27. Ferron M, McKee MD, Levine RL, Ducy P, Karsenty G (2012) Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone 50(2):568–575PubMedCrossRefGoogle Scholar
  28. Fisher JS, Gao J, Han D-H, Holloszy JO, Nolte LA (2002) Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab 282(1):E18–E23PubMedCrossRefGoogle Scholar
  29. Fukumoto S, Martin TJ (2009) Bone as an endocrine organ. Trends Endocrinol Metab 20(5):230–236PubMedCrossRefGoogle Scholar
  30. Funai K, Cartee GD (2009) Inhibition of contraction-stimulated AMP-activated protein kinase inhibits contraction-stimulated increases in PAS-TBC1D1 and glucose transport without altering PAS-AS160 in rat skeletal muscle. Diabetes 58(5):1096–1104PubMedPubMedCentralCrossRefGoogle Scholar
  31. Funai K, Schweitzer GG, Castorena CM, Kanzaki M, Cartee GD (2010) In vivo exercise followed by in vitro contraction additively elevates subsequent insulin-stimulated glucose transport by rat skeletal muscle. Am J Physiol Endocrinol Metab 298(5):E999–E1010PubMedPubMedCentralCrossRefGoogle Scholar
  32. Geraghty KM, Chen S, Harthill JE et al (2007) Regulation of multisite phosphorylation and 14-3-3 binding of AS160 in response to IGF-1, EGF. PMA and AICAR Biochem J 407(2):231–241PubMedGoogle Scholar
  33. Gomes TS, Aoike DT, Baria F, Graciolli FG, Moyses RM, Cuppari L (2017) Effect of aerobic exercise on markers of bone metabolism of overweight and obese patients with chronic kidney disease. J Ren Nutr 27(5):364–371PubMedCrossRefPubMedCentralGoogle Scholar
  34. Gupte AA, Sabek OM, Fraga D et al (2014) Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome. Endocrinology 155(12):4697–4705PubMedPubMedCentralCrossRefGoogle Scholar
  35. Han B, Zhu MJ, Ma C, Du M (2007) Rat hindlimb unloading down-regulates insulin like growth factor-1 signaling and AMP-activated protein kinase, and leads to severe atrophy of the soleus muscle. Appl Physiol Nutr Metab 32(6):1115–1123PubMedCrossRefPubMedCentralGoogle Scholar
  36. Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262PubMedPubMedCentralCrossRefGoogle Scholar
  37. Harslof T, Sikjaer T, Mosekilde L, Langdahl BL, Rejnmark L (2016) Correlations between changes in undercarboxylated osteocalcin and muscle function in hypoparathyroidism. Int J Endocrinol Metab 14(3):e38440PubMedPubMedCentralCrossRefGoogle Scholar
  38. Hauschka PV, Lian JB, Cole D, Gundberg CM (1989) Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69(3):990–1047PubMedCrossRefGoogle Scholar
  39. Hayashi Y, Kawakubo-Yasukochi T, Mizokami A et al (2017) Uncarboxylated osteocalcin induces antitumor immunity against mouse melanoma cell growth. J Cancer 8(13):2478PubMedPubMedCentralCrossRefGoogle Scholar
  40. Hemmings BA, Restuccia DF (2012) Pi3k-pkb/akt pathway. Cold Spring Harb Perspect Biol 4(9):a011189PubMedPubMedCentralCrossRefGoogle Scholar
  41. Higaki Y, Mikami T, Fujii N et al (2008) Oxidative stress stimulates skeletal muscle glucose uptake through a phosphatidylinositol 3-kinase-dependent pathway. Am J Physiol Endocrinol Metab 294(5):E889–EE97PubMedPubMedCentralCrossRefGoogle Scholar
  42. Hood MS, Little JP, Tarnopolsky MA, Myslik F, Gibala MJ (2011) Low-volume interval training improves muscle oxidative capacity in sedentary adults. Med Sci Sports Exerc 43(10):1849–1856PubMedCrossRefPubMedCentralGoogle Scholar
  43. Jacobsen SE, Nørskov-Lauritsen L, Thomsen ARB et al (2013) Delineation of the GPRC6A receptor signaling pathways using a mammalian cell line stably expressing the receptor. J Pharmacol Exp Ther 347(2):298–309PubMedCrossRefPubMedCentralGoogle Scholar
  44. Jensen TE, Schjerling P, Viollet B, Wojtaszewski JF, Richter EA (2008) AMPK α1 activation is required for stimulation of glucose uptake by twitch contraction, but not by H2O2, in mouse skeletal muscle. PLoS One 3(5):e2102PubMedPubMedCentralCrossRefGoogle Scholar
  45. Kelley DE, He J, Menshikova EV, Ritov VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51(10):2944–2950PubMedCrossRefPubMedCentralGoogle Scholar
  46. Kennedy JW, Hirshman MF, Gervino EV et al (1999) Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes. Diabetes 48(5):1192–1197PubMedCrossRefPubMedCentralGoogle Scholar
  47. Kim J, Kundu M, Viollet B, Guan K-L (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141PubMedPubMedCentralCrossRefGoogle Scholar
  48. Kingwell BA, Formosa M, Muhlmann M, Bradley SJ, McConell GK (2002) Nitric oxide synthase inhibition reduces glucose uptake during exercise in individuals with type 2 diabetes more than in control subjects. Diabetes 51(8):2572–2580PubMedCrossRefPubMedCentralGoogle Scholar
  49. Kjøbsted R, Treebak JT, Fentz J et al (2015) Prior AICAR stimulation increases insulin sensitivity in mouse skeletal muscle in an AMPK-dependent manner. Diabetes 64(6):2042–2055PubMedCrossRefPubMedCentralGoogle Scholar
  50. Kjøbsted R, Munk-Hansen N, Birk JB et al (2017) Enhanced muscle insulin sensitivity after contraction/exercise is mediated by AMPK. Diabetes 66(3):598–612PubMedCrossRefPubMedCentralGoogle Scholar
  51. Kramer HF, Goodyear LJ (2007) Exercise, MAPK, and NF-κB signaling in skeletal muscle. J Appl Physiol 103(1):388–395PubMedCrossRefPubMedCentralGoogle Scholar
  52. Lee AD, Hansen PA, Holloszy JO (1995) Wortmannin inhibits insulin-stimulated but not contraction-stimulated glucose transport activity in skeletal muscle. FEBS Lett 361(1):51–54PubMedCrossRefPubMedCentralGoogle Scholar
  53. Lee NK, Sowa H, Hinoi E et al (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130(3):456–469PubMedPubMedCentralCrossRefGoogle Scholar
  54. Lee SW, Jo HH, Kim MR, Kim JH, You YO (2015) Association between osteocalcin and metabolic syndrome in postmenopausal women. Arch Gynecol Obstet 292(3):673–681PubMedCrossRefPubMedCentralGoogle Scholar
  55. Levinger I, Zebaze R, Jerums G, Hare DL, Selig S, Seeman E (2011) The effect of acute exercise on undercarboxylated osteocalcin in obese men. Osteoporos Int 22(5):1621–1626PubMedCrossRefPubMedCentralGoogle Scholar
  56. Levinger I, Jerums G, Stepto NK et al (2014a) The effect of acute exercise on undercarboxylated osteocalcin and insulin sensitivity in obese men. J Bone Miner Res 29(12):2571–2576PubMedCrossRefPubMedCentralGoogle Scholar
  57. Levinger I, Scott D, Nicholson GC et al (2014b) Undercarboxylated osteocalcin, muscle strength and indices of bone health in older women. Bone 64:8–12PubMedCrossRefPubMedCentralGoogle Scholar
  58. Levinger I, Lin X, Zhang X et al (2016a) The effects of muscle contraction and recombinant osteocalcin on insulin sensitivity ex vivo. Osteoporos Int 27(2):653–663CrossRefGoogle Scholar
  59. Levinger I, Seeman E, Jerums G et al (2016b) Glucose-loading reduces bone remodeling in women and osteoblast function in vitro. Phys Rep 4(3):e12700CrossRefGoogle Scholar
  60. Levinger I, Brennan-Speranza T, Zulli A et al (2017a) Multifaceted interaction of bone, muscle, lifestyle interventions and metabolic and cardiovascular disease: role of osteocalcin. Osteoporos Int 28:1–9CrossRefGoogle Scholar
  61. Levinger I, Yan X, Bishop D et al (2017b) The influence of α-actinin-3 deficiency on bone remodelling markers in young men. Bone 98:26–30PubMedCrossRefPubMedCentralGoogle Scholar
  62. Li H, Zhou B, Xu L et al (2014) The reciprocal interaction between autophagic dysfunction and ER stress in adipose insulin resistance. Cell Cycle 13(4):565–579PubMedCrossRefPubMedCentralGoogle Scholar
  63. Li J, Zhang H, Yang C, Li Y, Dai Z (2016) An overview of osteocalcin progress. J Bone Miner Metab 34(4):367–379PubMedCrossRefPubMedCentralGoogle Scholar
  64. Lin X, Hanson E, Betik AC, Brennan-Speranza TC, Hayes A, Levinger I (2016) Hindlimb immobilization, but not castration, induces reduction of undercarboxylated osteocalcin associated with muscle atrophy in rats. J Bone Miner Res 31(11):1967–1978PubMedCrossRefPubMedCentralGoogle Scholar
  65. Lin X, Parker L, Mclennan E et al (2017) Recombinant uncarboxylated osteocalcin per se enhances mouse skeletal muscle glucose uptake in both extensor digitorum longus and soleus muscles. Front Endocrinol 8:330CrossRefGoogle Scholar
  66. Lin X, Parker L, Mclennan E et al (2018a) Uncarboxylated osteocalcin enhances glucose uptake ex vivo in insulin-stimulated mouse oxidative but not glycolytic muscle. Calcif Tissue Int 103:1–8CrossRefGoogle Scholar
  67. Lin X, Brennan-Speranza T, Levinger I, Yeap B (2018b) Undercarboxylated osteocalcin: experimental and human evidence for a role in glucose homeostasis and muscle regulation of insulin sensitivity. Nutrients 10(7):847PubMedCentralCrossRefGoogle Scholar
  68. Liu J, Peng Y, Cui Z et al (2012) Depressed mitochondrial biogenesis and dynamic remodeling in mouse tibialis anterior and gastrocnemius induced by 4-week hindlimb unloading. IUBMB Life 64(11):901–910PubMedCrossRefPubMedCentralGoogle Scholar
  69. Liu X, Greer C, Secombe J (2014) KDM5 interacts with Foxo to modulate cellular levels of oxidative stress. PLoS Genet 10(10):e1004676PubMedPubMedCentralCrossRefGoogle Scholar
  70. Liu S, Gao F, Wen L et al (2017) Osteocalcin induces proliferation via positive activation of the PI3K/Akt, P38 MAPK pathways and promotes differentiation through activation of the GPRC6A-ERK1/2 pathway in C2C12 myoblast cells. Cell Physiol Biochem 43(3):1100–1112PubMedCrossRefPubMedCentralGoogle Scholar
  71. Manning BD, Toker A (2017) AKT/PKB signaling: navigating the network. Cell 169(3):381–405PubMedPubMedCentralCrossRefGoogle Scholar
  72. Mayr B, Montminy M (2001) Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2(8):599–609PubMedCrossRefPubMedCentralGoogle Scholar
  73. McCabe KM, Adams MA, Holden RM (2013) Vitamin K status in chronic kidney disease. Nutrients 5(11):4390–4398PubMedPubMedCentralCrossRefGoogle Scholar
  74. Mera P, Laue K, Ferron M et al (2016a) Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metab 23(6):1078–1092PubMedPubMedCentralCrossRefGoogle Scholar
  75. Mera P, Laue K, Wei J, Berger JM, Karsenty G (2016b) Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Mol Metab 5(10):1042–1047PubMedPubMedCentralCrossRefGoogle Scholar
  76. Meyer C, Dostou JM, Welle SL, Gerich JE (2002) Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis. Am J Physiol Endocrinol Metab 282(2):E419–EE27PubMedCrossRefPubMedCentralGoogle Scholar
  77. Mîinea CP, Sano H, Kane S et al (2005) AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem J 391(1):87–93PubMedPubMedCentralCrossRefGoogle Scholar
  78. Mizokami A, Yasutake Y, Gao J et al (2013) Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice. PLoS One 8(2):e57375PubMedPubMedCentralCrossRefGoogle Scholar
  79. Mizokami A, Yasutake Y, Higashi S et al (2014) Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion. Bone 69:68–79PubMedCrossRefPubMedCentralGoogle Scholar
  80. Mounier R, Théret M, Lantier L, Foretz M, Viollet B (2015) Expanding roles for AMPK in skeletal muscle plasticity. Trends Endocrinol Metab 26(6):275–286PubMedCrossRefGoogle Scholar
  81. Mu J, Brozinick JT, Valladares O, Bucan M, Birnbaum MJ (2001) A role for AMP-activated protein kinase in contraction-and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 7(5):1085–1094PubMedCrossRefGoogle Scholar
  82. Neufer PD, Bamman MM, Muoio DM et al (2015) Understanding the cellular and molecular mechanisms of physical activity-induced health benefits. Cell Metab 22(1):4–11PubMedCrossRefGoogle Scholar
  83. Neve A, Corrado A, Cantatore FP (2013) Osteocalcin: skeletal and extra-skeletal effects. J Cell Physiol 228(6):1149–1153PubMedCrossRefGoogle Scholar
  84. Nordin M, Frankel VH (2001) Basic biomechanics of the musculoskeletal system. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  85. Oury F, Sumara G, Sumara O et al (2011) Endocrine regulation of male fertility by the skeleton. Cell 144(5):796–809PubMedPubMedCentralCrossRefGoogle Scholar
  86. Oury F, Khrimian L, Denny CA et al (2013) Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 155(1):228–241PubMedCrossRefGoogle Scholar
  87. Parker L, Lin X, Garnham A et al (2018) Glucocorticoid-induced insulin resistance in men is associated with suppressed Undercarboxylated osteocalcin. J Bone Miner Res 34(1):49–58PubMedCrossRefGoogle Scholar
  88. Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8(8):457–465PubMedCrossRefGoogle Scholar
  89. Pedersen B, Steensberg A, Fischer C et al (2004) The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor? Proc Nutr Soc 63(2):263–267PubMedCrossRefGoogle Scholar
  90. Pehmøller C, Treebak JT, Birk JB et al (2009) Genetic disruption of AMPK signaling abolishes both contraction-and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscle. Am J Physiol Endocrinol Metab 297(3):E665–EE75PubMedPubMedCentralCrossRefGoogle Scholar
  91. Perdomo G, Martinez-Brocca MA, Bhatt BA, Brown NF, O’Doherty RM, Garcia-Ocaña A (2008) Hepatocyte growth factor is a novel stimulator of glucose uptake and metabolism in skeletal muscle cells. J Biol Chem 283(20):13700–13706PubMedPubMedCentralCrossRefGoogle Scholar
  92. Pi M, Kapoor K, Ye R et al (2016) Evidence for osteocalcin binding and activation of GPRC6A in β-cells. Endocrinology 157(5):1866–1880PubMedPubMedCentralCrossRefGoogle Scholar
  93. Rached M-T, Kode A, Silva BC et al (2010) FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J Clin Invest 120(1):357PubMedCrossRefGoogle Scholar
  94. Richter EA, Hargreaves M (2013) Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev 93(3):993–1017PubMedCrossRefGoogle Scholar
  95. Richter EA, Garetto LP, Goodman MN, Ruderman NB (1982) Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin. J Clin Invest 69(4):785PubMedPubMedCentralCrossRefGoogle Scholar
  96. Rossetti ML, Steiner JL, Gordon BS (2017) Androgen-mediated regulation of skeletal muscle protein balance. Mol Cell Endocrinol 447:35–44PubMedPubMedCentralCrossRefGoogle Scholar
  97. Rowland AF, Fazakerley DJ, James DE (2011) Mapping insulin/GLUT4 circuitry. Traffic 12(6):672–681PubMedCrossRefGoogle Scholar
  98. Rueda P, Harley E, Lu Y et al (2016) Murine GPRC6A mediates cellular responses to L-amino acids, but not osteocalcin variants. PLoS One 11(1):e0146846PubMedPubMedCentralCrossRefGoogle Scholar
  99. Sajan MP, Bandyopadhyay G, Miura A et al (2010) AICAR and metformin, but not exercise, increase muscle glucose transport through AMPK-, ERK-, and PDK1-dependent activation of atypical PKC. Am J Physiol Endocrinol Metab 298(2):E179–EE92PubMedCrossRefGoogle Scholar
  100. Sakuma K, Aoi W, Yamaguchi A (2017) Molecular mechanism of sarcopenia and cachexia: recent research advances. Pflugers Arch 469(5–6):573–591PubMedCrossRefGoogle Scholar
  101. Sanchez AM, Csibi A, Raibon A et al (2012) AMPK promotes skeletal muscle autophagy through activation of forkhead FoxO3a and interaction with Ulk1. J Cell Biochem 113(2):695–710PubMedCrossRefGoogle Scholar
  102. Sandri M (2008) Signaling in muscle atrophy and hypertrophy. Physiology 23(3):160–170PubMedCrossRefGoogle Scholar
  103. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101PubMedCrossRefGoogle Scholar
  104. Sartorelli V, Fulco M (2004) Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy. Sci STKE 2004(244):re11PubMedGoogle Scholar
  105. Schiaffino S, Reggiani C (2011) Fiber types in mammalian skeletal muscles. Physiol Rev 91(4):1447–1531PubMedPubMedCentralCrossRefGoogle Scholar
  106. Senf SM, Sandesara PB, Reed SA, Judge AR (2011) p300 acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle. Am J Phys Cell Phys 300(6):C1490–CC501CrossRefGoogle Scholar
  107. Sheffield-Moore M, Urban RJ (2004) An overview of the endocrinology of skeletal muscle. Trends Endocrinol Metab 15(3):110–115PubMedCrossRefGoogle Scholar
  108. Shen H, Grimston S, Civitelli R, Thomopoulos S (2015) Deletion of connexin43 in osteoblasts/osteocytes leads to impaired muscle formation in mice. J Bone Miner Res 30(4):596–605PubMedPubMedCentralCrossRefGoogle Scholar
  109. Sjøberg KA, Frøsig C, Kjøbsted R et al (2017) Exercise increases human skeletal muscle insulin sensitivity via coordinated increases in microvascular perfusion and molecular signaling. Diabetes 66:1501PubMedCrossRefGoogle Scholar
  110. Sokoll LJ, Booth SL, O’Brien ME, Davidson KW, Tsaioun KI, Sadowski JA (1997) Changes in serum osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects. Am J Clin Nutr 65(3):779–784PubMedCrossRefGoogle Scholar
  111. Spiegelman BM (1999) Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators. In: Novartis foundation symposium; 2007. John Wiley, Chichester/New York, p 60Google Scholar
  112. Taylor EB, An D, Kramer HF et al (2008) Discovery of TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling nexus in mouse skeletal muscle. J Biol Chem 283(15):9787–9796PubMedPubMedCentralCrossRefGoogle Scholar
  113. Treebak JT, Glund S, Deshmukh A et al (2006) AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits. Diabetes 55(7):2051–2058PubMedCrossRefPubMedCentralGoogle Scholar
  114. Trounce I, Byrne E, Marzuki S (1989) Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing. Lancet 333(8639):637–639CrossRefGoogle Scholar
  115. Tsuka S, Aonuma F, Higashi S et al (2015) Promotion of insulin-induced glucose uptake in C2C12 myotubes by osteocalcin. Biochem Biophys Res Commun 459(3):437–442PubMedCrossRefPubMedCentralGoogle Scholar
  116. Vilchinskaya NA, Mochalova EP, Nemirovskaya TL, Mirzoev TM, Turtikova OV, Shenkman BS (2017) Rapid decline in Myhc I (β) mrna expression in rat soleus during hindlimb unloading is associated with Ampk dephosphorylation. J Physiol 595(23):7123–7134PubMedPubMedCentralCrossRefGoogle Scholar
  117. Watt MJ, Holmes AG, Pinnamaneni SK et al (2006) Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab 290(3):E500–E5E8PubMedCrossRefGoogle Scholar
  118. Wei J, Ferron M, Clarke CJ et al (2014) Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. J Clin Invest 124(4):1781PubMedCentralCrossRefPubMedGoogle Scholar
  119. Wiernsperger N (2005) Is non-insulin dependent glucose uptake a therapeutic alternative? Part 1: physiology, mechanisms and role of non insulin-dependent glucose uptake in type 2 diabetes. Diabetes Metab 31(5):415–426PubMedCrossRefGoogle Scholar
  120. Wolf G (1996) Function of the bone protein osteocalcin: definitive evidence. Nutr Rev 54(10):332–333PubMedCrossRefGoogle Scholar
  121. Wolfe RR (2006) The underappreciated role of muscle in health and disease. Am J Clin Nutr 84(3):475–482PubMedCrossRefGoogle Scholar
  122. Wu M, Falasca M, Blough ER (2011) Akt/protein kinase B in skeletal muscle physiology and pathology. J Cell Physiol 226(1):29–36PubMedCrossRefGoogle Scholar
  123. Yamauchi T, Kamon J, Minokoshi Y et al (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8(11):1288–1295PubMedCrossRefGoogle Scholar
  124. Yoshihara T, Machida S, Kurosaka Y et al (2015) Immobilization-induced rat skeletal muscle atrophy enhances histone modification through HDAC4. FASEB J 29(1 Supplement):877.5Google Scholar
  125. Yoshihara T, Machida S, Naito H (2016) Disuse-induced nuclear accumulation of histone deacetylase 4 in rat skeletal muscle. Musculoskelet Regener 2:e1368Google Scholar
  126. Yoshizawa T, Hinoi E, Jung DY et al (2009) The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts. J Clin Invest 119(9):2807–2817PubMedPubMedCentralCrossRefGoogle Scholar
  127. Zhong G, Li Y, Li H et al (2016) Simulated microgravity and recovery-induced remodeling of the left and right ventricle. Front Physiol 7:274PubMedPubMedCentralCrossRefGoogle Scholar
  128. Zhou B, Li H, Xu L, Zang W, Wu S, Sun H (2013a) Osteocalcin reverses endoplasmic reticulum stress and improves impaired insulin sensitivity secondary to diet-induced obesity through nuclear factor-κB signaling pathway. Endocrinology 154(3):1055–1068PubMedCrossRefGoogle Scholar
  129. Zhou B, Li H, Liu J et al (2013b) Intermittent injections of osteocalcin reverse autophagic dysfunction and endoplasmic reticulum stress resulting from diet-induced obesity in the vascular tissue via the NFκB-p65-dependent mechanism. Cell Cycle 12(12):1901–1913PubMedPubMedCentralCrossRefGoogle Scholar
  130. Zhou B, Li H, Liu J et al (2016) Autophagic dysfunction is improved by intermittent administration of osteocalcin in obese mice. Int J Obes 40(5):833–843CrossRefGoogle Scholar
  131. Zurlo F, Larson K, Bogardus C, Ravussin E (1990) Skeletal muscle metabolism is a major determinant of resting energy expenditure. J Clin Invest 86(5):1423PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institute for Health and Sport (IHES)Victoria UniversityMelbourneAustralia
  2. 2.Australian Institute for Musculoskeletal Science (AIMSS)The University of Melbourne and Western HealthSt. AlbansAustralia
  3. 3.Department of Medicine-Western HealthThe University of MelbourneSt. AlbansAustralia
  4. 4.Bosch InstituteThe University of SydneySydneyAustralia
  5. 5.Department of Medicine-Western HealthMelbourne Medical School, The University of MelbourneSt. AlbansAustralia

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