The effects of muscle contraction and recombinant osteocalcin on insulin sensitivity ex vivo

Levinger, Itamar; Lin, Xuzhu; ZHANG, XUEXIN; Brennan‐Speranza, Tara C.; Volpato, Bruna Heloisa; Hayes, Alan; Jerums, George; Seeman, Ego; McConell, Glenn K.

doi:10.1007/s00198-015-3273-0

Cited by 44 publications

(44 citation statements)

References 35 publications

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“…Accumulating evidence suggests that ucOC may exert its beneficial effects on muscle insulin sensitivity through the upregulation of activation and/or expression of mTORC2‐Akt‐AS160 cascade . In support, we report that ucOC increased insulin‐stimulated phosphorylation of mTOR Ser2481 in both CS‐affected EDL and soleus muscles, and Akt Ser473 in CS‐affected EDL muscle.…”

Section: Discussionsupporting

confidence: 84%

“…The adverse metabolic effects of short‐term GC treatment on muscle may be partly based on the functional perturbation of bone cells, leading to the reduction of circulating ucOC—a hormone secreted by osteoblasts. Emerging evidence shows that ucOC favors muscle insulin sensitivity, at least in mice . ucOC administration not only enhances muscle insulin sensitivity in healthy animals, but also partially restores insulin sensitivity in insulin‐resistant animals that commonly exhibit low ucOC levels .…”

Section: Introductionmentioning

confidence: 99%

“…Our recent findings suggest that ucOC likely has effects on insulin‐stimulated glucose uptake (ISGU) of healthy mouse muscle in a muscle type‐specific manner. For example, ucOC enhances ISGU in soleus muscle only at rest, whereas in EDL muscle ucOC only enhances ISGU following ex vivo muscle contraction . Therefore, the possible rescuing effect of ucOC on insulin‐resistant muscle, as well as the molecular mechanism, may also be muscle type‐dependant.…”

Section: Introductionmentioning

confidence: 99%

“…Emerging evidence shows that ucOC favors muscle insulin sensitivity, at least in mice. (5)(6)(7) ucOC administration not only enhances muscle insulin sensitivity in healthy animals, but also partially restores insulin sensitivity in insulin-resistant animals that commonly exhibit low ucOC levels. (8)(9)(10) We recently reported that acute GC-induced insulin resistance in humans (20 mg of prednisolone) strongly correlated with suppressed serum ucOC and ucOC-associated signaling pathways in muscle.…”

Section: Introductionmentioning

confidence: 99%

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Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

Lin

Parker

McLennan

et al. 2019

Journal of Bone and Mineral Research

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Short‐term administration of glucocorticoids (GCs) impairs muscle insulin sensitivity at least in part via the reduction of undercarboxylated osteocalcin (ucOC). However, whether ucOC treatment reverses the GC‐induced muscle insulin resistance remains unclear. To test the hypothesis that ucOC directly ameliorates impaired insulin‐stimulated glucose uptake (ISGU) induced by short‐term GC administration in mice muscle and to identify the molecular mechanisms, mice were implanted with placebo or corticosterone (CS) slow‐release pellets. Two days post‐surgery, insulin‐tolerance tests (ITTs) were performed. On day 3, serum was collected and extensor digitorum longus (EDL) and soleus muscles were isolated and treated ex vivo with vehicle, ucOC (30 ng/mL), insulin (60 µU/mL), or both. Circulating hormone levels, muscle glucose uptake, and muscle signaling proteins were assessed. CS administration reduced both serum osteocalcin and ucOC levels, whole‐body insulin sensitivity, and muscle ISGU in EDL. Ex vivo ucOC treatment restored ISGU in CS‐affected muscle, without increasing non‐insulin‐stimulated glucose uptake. In CS‐affected EDL muscle, ucOC enhanced insulin action on phosphorylated (p‐)protein kinase B (Akt)Ser473and the p‐extracellular signal‐regulated kinase isoform 2 (ERK2)Thr202/Tyr204/total (t)ERK2 ratio, which correlated with ISGU. In CS‐affected soleus muscle, ucOC enhanced insulin action on p‐mammalian target of rapamycin (mTOR)Ser2481, the p‐mTORSer2481/tmTOR ratio, p‐Akt substrate of 160kD (AS160)Thr642, and p‐protein kinase C (PKC) (pan)Thr410, which correlated with ISGU. Furthermore, p‐PKC (pan)Thr410 correlated with p‐AktSer473 and p‐AS160Thr642. ucOC exerts direct insulin‐sensitizing effects on CS‐affected mouse muscle, likely through an enhancement in activity of key proteins involved in both insulin and ucOC signaling pathways. Furthermore, these effects are muscle type‐dependent. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

Lin

Parker

McLennan

et al. 2019

Journal of Bone and Mineral Research

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“…(37) After the completion of ex vivo contraction experiments, the EDL and soleus were removed from the bath, blotted dried, cut free of tendon, and weighed. The EDL and soleus muscles from both legs were excised tendon to tendon and ex vivo contraction was conducted as described.…”

Section: Ex Vivo Muscle Contraction and Sample Collectionmentioning

confidence: 99%

Hindlimb Immobilization, But Not Castration, Induces Reduction of Undercarboxylated Osteocalcin Associated With Muscle Atrophy in Rats

Lin

Hanson

Betik

et al. 2016

Journal of Bone and Mineral Research

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Undercarboxylated osteocalcin (ucOC) has been implicated in skeletal muscle insulin sensitivity and function. However, whether muscle mass and strength loss in atrophic conditions is related to a reduction in ucOC is not clear. We hypothesized that both immobilization and testosterone depletion would lead to reductions in ucOC, associated with not only the degree of muscle atrophy but also changes to atrophy signaling pathway(s) in male rats. We subjected 8-week-old male Fischer (F344) rats to 7 days of hindlimb immobilization 10 days after castration surgery. Hindlimb immobilization, but not castration, resulted in a significant reduction in ucOC (30%) and lower ucOC was correlated with the degree of muscle loss and muscle weakness. ucOC levels, the expression of ucOC-sensitive receptor G protein-coupled receptor, class C, group 6, member A (GPRC6A), as well as the activity of extracellular signal-regulated kinase (ERK) and 5' adenosine monophosphate-activated protein kinase (AMPK) were associated with the expression and activity of a number of proteins in the mammalian target of rapamycin complex 1 (mTORC1) and Forkhead Box O (FOXO) signaling pathways in a muscle type-specific manner. These data suggest that ucOC may have other effects on skeletal muscle in addition to its insulin sensitizing effect. © 2016 American Society for Bone and Mineral Research.

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Osteocalcin and the physiology of danger

Berger

Karsenty

2022

FEBS Letters

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Bone biology has long been driven by the question as to what molecules affect cell differentiation or the functions of bone. Exploring this issue has been an extraordinarily powerful way to improve our knowledge of bone development and physiology. More recently, a second question has emerged: does bone have other functions besides making bone? Addressing this conundrum revealed that the bone‐derived hormone osteocalcin affects a surprisingly large number of organs and physiological processes, including acute stress response. This review will focus on this emerging aspect of bone biology taking osteocalcin as a case study and will show how classical and endocrine functions of bone help to define a new functional identity for this tissue.

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The effects of muscle contraction and recombinant osteocalcin on insulin sensitivity ex vivo

Abstract: GPRC6A, the likely receptor of osteocalcin (OC), is expressed in mouse muscle. ucOC treatment augments insulin-stimulated skeletal muscle glucose uptake in C2C12 myotubes and following ex vivo muscle contraction. ucOC may partly account for the insulin sensitizing effect of exercise.

Cited by 44 publications

References 35 publications

Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

Hindlimb Immobilization, But Not Castration, Induces Reduction of Undercarboxylated Osteocalcin Associated With Muscle Atrophy in Rats

Osteocalcin and the physiology of danger

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