Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts

Chowdhury, Subrata; Schulz, Logan C; Palmisano, Biagio; Singh, Parminder; Berger, Julian; Yadav, Vijay K.; Mera, Paula; Ellingsgaard, Helga; Hidalgo, Juan; Brüning, Jens C.; Karsenty, Gérard

doi:10.1172/jci133572

Cited by 90 publications

(93 citation statements)

References 34 publications

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“…This effect may be due to the fact that osteocalcin promotes muscle protein synthesis, as indicated by studies in cultured myotubes, but the signaling pathway involved has not been determined. It was suggested that osteocalcin is a central component of a muscle-bone-muscle endocrine axis, whereby interleukin 6 (IL-6) released by skeletal muscle during exercise acts on osteoblasts to induce the release of bioactive osteocalcin that in turn acts on muscle cells [25]. However, recent studies using new osteocalcin knockout models have not confirmed an endocrine role of osteocalcin nor a pro-hypertrophic effect on skeletal muscle [26,27].…”

Section: Osteocalcinmentioning

confidence: 99%

Molecular Mechanisms of Skeletal Muscle Hypertrophy

Schiaffino

Reggiani

Akimoto

et al. 2021

JND

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Skeletal muscle hypertrophy can be induced by hormones and growth factors acting directly as positive regulators of muscle growth or indirectly by neutralizing negative regulators, and by mechanical signals mediating the effect of resistance exercise. Muscle growth during hypertrophy is controlled at the translational level, through the stimulation of protein synthesis, and at the transcriptional level, through the activation of ribosomal RNAs and muscle-specific genes. mTORC1 has a central role in the regulation of both protein synthesis and ribosomal biogenesis. Several transcription factors and co-activators, including MEF2, SRF, PGC-1α4, and YAP promote the growth of the myofibers. Satellite cell proliferation and fusion is involved in some but not all muscle hypertrophy models.

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Section: Osteocalcinmentioning

confidence: 99%

Molecular Mechanisms of Skeletal Muscle Hypertrophy

Schiaffino

Reggiani

Akimoto

et al. 2021

JND

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“…Moreover, exercise was reported to increase circulating interleukin 6 (IL-6), which originates from muscle. Further, IL-6 was shown to induce osteoclast differentiation and bone resorption, increase the circulation of uncarboxylated Ocn, and promote the uptake and catabolism of glucose and fatty acids in myofibers during exercise in an Ocn-dependent manner [ 104 ].…”

Section: Function Of Ocn In Testosterone Synthesis and Muscle Massmentioning

confidence: 99%

Functions of Osteocalcin in Bone, Pancreas, Testis, and Muscle

Komori

2020

IJMS

175

108

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Osteocalcin (Ocn), which is specifically produced by osteoblasts, and is the most abundant non-collagenous protein in bone, was demonstrated to inhibit bone formation and function as a hormone, which regulates glucose metabolism in the pancreas, testosterone synthesis in the testis, and muscle mass, based on the phenotype of Ocn−/− mice by Karsenty’s group. Recently, Ocn−/− mice were newly generated by two groups independently. Bone strength is determined by bone quantity and quality. The new Ocn−/− mice revealed that Ocn is not involved in the regulation of bone formation and bone quantity, but that Ocn regulates bone quality by aligning biological apatite (BAp) parallel to the collagen fibrils. Moreover, glucose metabolism, testosterone synthesis and spermatogenesis, and muscle mass were normal in the new Ocn−/− mice. Thus, the function of Ocn is the adjustment of growth orientation of BAp parallel to the collagen fibrils, which is important for bone strength to the loading direction of the long bone. However, Ocn does not play a role as a hormone in the pancreas, testis, and muscle. Clinically, serum Ocn is a marker for bone formation, and exercise increases bone formation and improves glucose metabolism, making a connection between Ocn and glucose metabolism.

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“…Importantly and relevant for those patients treated with tocilizumab, the results suggest that IL-6 receptor blockade appears to have no effect on plasma levels of CTX and P1NP. Of note, samples from study 2 were recently analyzed for osteocalcin [ 17 ]. The analysis showed that 12 weeks of exercise training increased levels of osteocalcin and, moreover, that combining exercise training with IL-6 receptor blockade prevented exercise from increasing osteocalcin levels.…”

Section: Discussionmentioning

confidence: 99%

“…We first explored if endogenous IL-6 contributes to exercise and meal induced changes in plasma CTX and P1NP levels. A single bout of exercise has been reported to increase markers of bone resorption in humans [ 16 ] and long-term exercise training has been shown to increase bone formation marker osteocalcin in an IL-6 dependent manner [ 17 ]. In contrast to exercise, food intake reduces markers of bone resorption [ 18 ].…”

mentioning

confidence: 99%

Interleukin-6 May Not Affect Bone Resorption Marker CTX or Bone Formation Marker P1NP in Humans

Lehrskov

Kjeldsen

Lyngbæk

et al. 2020

Journal of the Endocrine Society

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Abstract Context Interleukin 6 (IL-6) contributes to bone remodeling in preclinical studies. Clinical trials investigating the role of IL-6 in bone remodeling are limited. Objective To investigate if IL-6 regulates bone remodeling in humans. Design Plasma concentrations of the bone resorption marker, carboxy-terminal type I collagen crosslinks (CTX) and of the bone formation marker, procollagen type 1 N-terminal propeptide (P1NP) were measured during a mixed meal tolerance test (MMTT) in three placebo-controlled human studies. Participants Five healthy individuals participated in study 1, 52 obese individuals in study 2, and 10 healthy individuals in study 3. Interventions Study 1 was a single-blinded cross-over study consisting of a one-hour infusion of saline (placebo) or the IL-6 receptor antibody tocilizumab followed by an exercise bout. Study 2 was a randomized, double-blinded 12-week exercise training intervention study. Participants received infusions of saline or tocilizumab. Study 3 was a randomized, double-blinded, cross-over study consisting of 30 minutes infusion of saline or IL-6. Main outcomes measures Effect of IL-6 on CTX levels. Results CTX was significantly (P<0.01) decreased during MMTTs in all three studies. Treatment with tocilizumab did not affect exercise or meal induced changes in plasma CTX or P1NP concentrations acutely (study 1) or after a 12-week treatment period (study 2). Exogenous IL-6 had no effect on CTX or P1NP plasma concentrations (study 3). Conclusions IL-6 may not regulate bone remodeling in humans. Précis Interleukin-6 (IL-6) plays a role in human metabolism and disease and IL-6 based therapy exists. It is discussed if IL-6 regulates bone metabolism in humans. We find that IL-6 does not affect CTX or P1NP, markers of bone turnover, in humans.

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Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts

Cited by 90 publications

References 34 publications

Molecular Mechanisms of Skeletal Muscle Hypertrophy

Molecular Mechanisms of Skeletal Muscle Hypertrophy

Functions of Osteocalcin in Bone, Pancreas, Testis, and Muscle

Interleukin-6 May Not Affect Bone Resorption Marker CTX or Bone Formation Marker P1NP in Humans

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