Skip to main content
SpringerLink
Log in

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

  • Chapter
  • First Online:
Osteosarcopenia: Bone, Muscle and Fat Interactions

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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):2–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alvim RO, Cheuhen MR, Machado SR, Sousa AGP, Santos PC (2015) General aspects of muscle glucose uptake. An Acad Bras Cienc 87(1):351–368

    Article  CAS  PubMed  Google Scholar 

  • 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–EE200

    Article  CAS  PubMed  Google Scholar 

  • 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):1155–1164

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ben-Sahra I, Manning BD (2017) mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol 45:72–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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–C403

    Article  Google Scholar 

  • Björnholm M, Zierath J (2005) Insulin signal transduction in human skeletal muscle: identifying the defects in type II diabetes. Biochem Soc Trans 33(2):354–357

    Article  PubMed  Google Scholar 

  • Bonaldo P, Sandri M (2013) Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech 6(1):25–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):4172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 5:99

    Article  PubMed  PubMed Central  Google Scholar 

  • Brotto M, Johnson ML (2014) Endocrine crosstalk between muscle and bone. Curr Osteoporos Rep 12(2):135–141

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):3154–3160

    Article  CAS  PubMed  Google Scholar 

  • 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):1981–1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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–EE59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cartee GD, Funai K (2009) Exercise and insulin: convergence or divergence at AS160 and TBC1D1? Exerc Sport Sci Rev 37(4):188

    Article  PubMed  PubMed Central  Google Scholar 

  • 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–E4E9

    Article  CAS  Google Scholar 

  • 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):3363–3373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charette S, McEvoy L, Pyka G et al (1991) Muscle hypertrophy response to resistance training in older women. J Appl Physiol 70(5):1912–1916

    Article  CAS  PubMed  Google Scholar 

  • 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):23554–23562

    Article  CAS  PubMed  Google Scholar 

  • 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):1000–1007

    Article  CAS  PubMed  Google Scholar 

  • Demling RH (2009) Nutrition, anabolism, and the wound healing process: an overview. Eplasty 9:e9

    PubMed  PubMed Central  Google Scholar 

  • 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):1814–1823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Devlin J, Horton E (1985) Effects of prior high-intensity exercise on glucose metabolism in normal and insulin-resistant men. Diabetes 34(10):973–979

    Article  CAS  PubMed  Google Scholar 

  • 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):163–179

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):5266–5270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):691–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):568–575

    Article  CAS  PubMed  Google Scholar 

  • 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–E23

    Article  CAS  PubMed  Google Scholar 

  • Fukumoto S, Martin TJ (2009) Bone as an endocrine organ. Trends Endocrinol Metab 20(5):230–236

    Article  CAS  PubMed  Google Scholar 

  • 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):1096–1104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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–E1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):231–241

    CAS  PubMed  Google Scholar 

  • 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):364–371

    Article  CAS  PubMed  Google Scholar 

  • Gupte AA, Sabek OM, Fraga D et al (2014) Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome. Endocrinology 155(12):4697–4705

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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):1115–1123

    Article  CAS  PubMed  Google Scholar 

  • Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):e38440

    Article  PubMed  PubMed Central  Google Scholar 

  • Hauschka PV, Lian JB, Cole D, Gundberg CM (1989) Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69(3):990–1047

    Article  CAS  PubMed  Google Scholar 

  • Hayashi Y, Kawakubo-Yasukochi T, Mizokami A et al (2017) Uncarboxylated osteocalcin induces antitumor immunity against mouse melanoma cell growth. J Cancer 8(13):2478

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hemmings BA, Restuccia DF (2012) Pi3k-pkb/akt pathway. Cold Spring Harb Perspect Biol 4(9):a011189

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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–EE97

    Article  CAS  PubMed  Google Scholar 

  • 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):1849–1856

    Article  CAS  PubMed  Google Scholar 

  • 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):298–309

    Article  CAS  PubMed  Google Scholar 

  • 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):e2102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kelley DE, He J, Menshikova EV, Ritov VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51(10):2944–2950

    Article  CAS  PubMed  Google Scholar 

  • 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):1192–1197

    Article  CAS  PubMed  Google Scholar 

  • 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):132–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):2572–2580

    Article  CAS  PubMed  Google Scholar 

  • 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):2042–2055

    Article  PubMed  CAS  Google Scholar 

  • Kjøbsted R, Munk-Hansen N, Birk JB et al (2017) Enhanced muscle insulin sensitivity after contraction/exercise is mediated by AMPK. Diabetes 66(3):598–612

    Article  PubMed  CAS  Google Scholar 

  • Kramer HF, Goodyear LJ (2007) Exercise, MAPK, and NF-κB signaling in skeletal muscle. J Appl Physiol 103(1):388–395

    Article  CAS  PubMed  Google Scholar 

  • 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):51–54

    Article  CAS  PubMed  Google Scholar 

  • Lee NK, Sowa H, Hinoi E et al (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130(3):456–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):673–681

    Article  CAS  PubMed  Google Scholar 

  • 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):1621–1626

    Article  CAS  PubMed  Google Scholar 

  • 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):2571–2576

    Article  CAS  PubMed  Google Scholar 

  • Levinger I, Scott D, Nicholson GC et al (2014b) Undercarboxylated osteocalcin, muscle strength and indices of bone health in older women. Bone 64:8–12

    Article  CAS  PubMed  Google Scholar 

  • 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):653–663

    Article  CAS  PubMed  Google Scholar 

  • 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):e12700

    Article  CAS  Google Scholar 

  • 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 28:1–9

    Article  CAS  Google Scholar 

  • Levinger I, Yan X, Bishop D et al (2017b) The influence of α-actinin-3 deficiency on bone remodelling markers in young men. Bone 98:26–30

    Article  CAS  PubMed  Google Scholar 

  • 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):565–579

    Article  PubMed  CAS  Google Scholar 

  • Li J, Zhang H, Yang C, Li Y, Dai Z (2016) An overview of osteocalcin progress. J Bone Miner Metab 34(4):367–379

    Article  CAS  PubMed  Google Scholar 

  • 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):1967–1978

    Article  CAS  PubMed  Google Scholar 

  • 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 8:330

    Article  Google Scholar 

  • 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 103:1–8

    Article  CAS  Google Scholar 

  • 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):847

    Article  PubMed Central  CAS  Google Scholar 

  • 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):901–910

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Greer C, Secombe J (2014) KDM5 interacts with Foxo to modulate cellular levels of oxidative stress. PLoS Genet 10(10):e1004676

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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):1100–1112

    Article  CAS  PubMed  Google Scholar 

  • Manning BD, Toker A (2017) AKT/PKB signaling: navigating the network. Cell 169(3):381–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayr B, Montminy M (2001) Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2(8):599–609

    Article  CAS  PubMed  Google Scholar 

  • McCabe KM, Adams MA, Holden RM (2013) Vitamin K status in chronic kidney disease. Nutrients 5(11):4390–4398

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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):1078–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1042–1047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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–EE27

    Article  CAS  PubMed  Google Scholar 

  • 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):87–93

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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):e57375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizokami A, Yasutake Y, Higashi S et al (2014) Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion. Bone 69:68–79

    Article  CAS  PubMed  Google Scholar 

  • Mounier R, Théret M, Lantier L, Foretz M, Viollet B (2015) Expanding roles for AMPK in skeletal muscle plasticity. Trends Endocrinol Metab 26(6):275–286

    Article  CAS  PubMed  Google Scholar 

  • 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):1085–1094

    Article  CAS  PubMed  Google Scholar 

  • 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):4–11

    Article  CAS  PubMed  Google Scholar 

  • Neve A, Corrado A, Cantatore FP (2013) Osteocalcin: skeletal and extra-skeletal effects. J Cell Physiol 228(6):1149–1153

    Article  CAS  PubMed  Google Scholar 

  • Nordin M, Frankel VH (2001) Basic biomechanics of the musculoskeletal system. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  • Oury F, Sumara G, Sumara O et al (2011) Endocrine regulation of male fertility by the skeleton. Cell 144(5):796–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oury F, Khrimian L, Denny CA et al (2013) Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 155(1):228–241

    Article  CAS  PubMed  Google Scholar 

  • 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):49–58

    Article  PubMed  CAS  Google Scholar 

  • Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8(8):457–465

    Article  CAS  PubMed  Google Scholar 

  • 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):263–267

    Article  CAS  PubMed  Google Scholar 

  • 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–EE75

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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):13700–13706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pi M, Kapoor K, Ye R et al (2016) Evidence for osteocalcin binding and activation of GPRC6A in β-cells. Endocrinology 157(5):1866–1880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):357

    Article  CAS  PubMed  Google Scholar 

  • Richter EA, Hargreaves M (2013) Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev 93(3):993–1017

    Article  CAS  PubMed  Google Scholar 

  • 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):785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossetti ML, Steiner JL, Gordon BS (2017) Androgen-mediated regulation of skeletal muscle protein balance. Mol Cell Endocrinol 447:35–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rowland AF, Fazakerley DJ, James DE (2011) Mapping insulin/GLUT4 circuitry. Traffic 12(6):672–681

    Article  CAS  PubMed  Google Scholar 

  • 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):e0146846

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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–EE92

    Article  CAS  PubMed  Google Scholar 

  • Sakuma K, Aoi W, Yamaguchi A (2017) Molecular mechanism of sarcopenia and cachexia: recent research advances. Pflugers Arch 469(5–6):573–591

    Article  CAS  PubMed  Google Scholar 

  • 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):695–710

    Article  CAS  PubMed  Google Scholar 

  • Sandri M (2008) Signaling in muscle atrophy and hypertrophy. Physiology 23(3):160–170

    Article  CAS  PubMed  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101

    Article  CAS  PubMed  Google Scholar 

  • Sartorelli V, Fulco M (2004) Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy. Sci STKE 2004(244):re11

    PubMed  Google Scholar 

  • Schiaffino S, Reggiani C (2011) Fiber types in mammalian skeletal muscles. Physiol Rev 91(4):1447–1531

    Article  CAS  PubMed  Google Scholar 

  • 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–CC501

    Article  CAS  Google Scholar 

  • Sheffield-Moore M, Urban RJ (2004) An overview of the endocrinology of skeletal muscle. Trends Endocrinol Metab 15(3):110–115

    Article  CAS  PubMed  Google Scholar 

  • 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):596–605

    Article  CAS  PubMed  Google Scholar 

  • 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 66:1501

    Article  PubMed  CAS  Google Scholar 

  • 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):779–784

    Article  CAS  PubMed  Google Scholar 

  • Spiegelman BM (1999) Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators. In: Novartis foundation symposium; 2007. John Wiley, Chichester/New York, p 60

    Google Scholar 

  • 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):9787–9796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):2051–2058

    Article  CAS  PubMed  Google Scholar 

  • Trounce I, Byrne E, Marzuki S (1989) Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing. Lancet 333(8639):637–639

    Article  Google Scholar 

  • 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):437–442

    Article  CAS  PubMed  Google Scholar 

  • 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):7123–7134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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–E5E8

    Article  CAS  PubMed  Google Scholar 

  • 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):1781

    Article  CAS  PubMed Central  Google Scholar 

  • 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):415–426

    Article  CAS  PubMed  Google Scholar 

  • Wolf G (1996) Function of the bone protein osteocalcin: definitive evidence. Nutr Rev 54(10):332–333

    Article  CAS  PubMed  Google Scholar 

  • Wolfe RR (2006) The underappreciated role of muscle in health and disease. Am J Clin Nutr 84(3):475–482

    Article  CAS  PubMed  Google Scholar 

  • Wu M, Falasca M, Blough ER (2011) Akt/protein kinase B in skeletal muscle physiology and pathology. J Cell Physiol 226(1):29–36

    Article  CAS  PubMed  Google Scholar 

  • 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):1288–1295

    Article  CAS  PubMed  Google Scholar 

  • 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):877.5

    Google Scholar 

  • Yoshihara T, Machida S, Naito H (2016) Disuse-induced nuclear accumulation of histone deacetylase 4 in rat skeletal muscle. Musculoskelet Regener 2:e1368

    Google Scholar 

  • 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):2807–2817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhong G, Li Y, Li H et al (2016) Simulated microgravity and recovery-induced remodeling of the left and right ventricle. Front Physiol 7:274

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):1055–1068

    Article  CAS  PubMed  Google Scholar 

  • 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):1901–1913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):833–843

    Article  CAS  Google Scholar 

  • 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):1423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia

    Xuzhu Lin, Alan Hayes, Glenn McConell & Itamar Levinger

  2. Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia

    Alan Hayes, Gustavo Duque & Itamar Levinger

  3. Department of Medicine-Western Health, The University of Melbourne, St. Albans, VIC, Australia

    Alan Hayes & Itamar Levinger

  4. Bosch Institute, The University of Sydney, Sydney, NSW, Australia

    Tara C. Brennan-Speranza

  5. Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, St. Albans, VIC, Australia

    Gustavo Duque

Authors
  1. Xuzhu Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Hayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Glenn McConell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gustavo Duque
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tara C. Brennan-Speranza
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Itamar Levinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Itamar Levinger .

Editor information

Editors and Affiliations

  1. Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia, Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, St. Albans, VIC, Australia

    Gustavo Duque

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Lin, X., Hayes, A., McConell, G., Duque, G., Brennan-Speranza, T.C., Levinger, I. (2019). The Endocrine Actions of Undercarboxylated Osteocalcin in Skeletal Muscle: Effects and Mechanisms. In: Duque, G. (eds) Osteosarcopenia: Bone, Muscle and Fat Interactions. Springer, Cham. https://doi.org/10.1007/978-3-030-25890-0_7

Download citation

Publish with us

Policies and ethics

Search

Navigation