Muscle injury, impaired muscle function and insulin resistance in Chromogranin a-knockout mice

K Tang, T Pasqua, A Biswas, SK Mahata, J Tang, A Tang, GK Bandyopadhyay, AP Sinha-Hikim, NW Chil, NJG Webster, A Corti, SK Mahata

Research output: Contribution to journalArticle

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Abstract

Chromogranin A (CgA) is widely expressed in endocrine and neuroendocrine tissues as well as in the central nervous system. We observed CgA expression (mRNA and protein) in the gastrocnemius (GAS) muscle and found that performance of CgA-deficient Chga-KO mice in treadmill exercise was impaired. Supplementation with CgA in Chga-KO mice restored exercise ability suggesting a novel role for endogenous CgA in skeletal muscle function. Chga-KO mice display (i) lack of exercise-induced stimulation of pAKT, pTBC1D1 and phospho-p38 kinase signaling, (ii) loss of GAS muscle mass, (iii) extensive formation of tubular aggregates (TA), (iv) disorganized cristae architecture in mitochondria, (v) increased expression of the inflammatory cytokines Tnfα, Il6 and Ifn?, and fibrosis. The impaired maximum running speed and endurance in the treadmill exercise in Chga-KO mice correlated with decreased glucose uptake and glycolysis, defects in glucose oxidation and decreased mitochondrial cytochrome C oxidase activity. The lack of adaptation to endurance training correlated with the lack of stimulation of p38MAPK that is known to mediate the response to tissue damage. As CgA sorts proteins to the regulated secretory pathway, we speculate that lack of CgA could cause misfolding of membrane proteins inducing aggregation of sarcoplasmic reticulum (SR) membranes and formation of tubular aggregates that is observed in Chga-KO mice. In conclusion, CgA deficiency renders the muscle energy deficient, impairs performance in treadmill exercise and prevents regeneration after exercise-induced tissue damage. © 2017 Society for Endocrinology.
Original languageEnglish
Pages (from-to)137-153
Number of pages17
JournalJournal of Endocrinology
Volume232
Issue number2
DOIs
Publication statusPublished - 2017

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Chromogranins
Chromogranin A
Knockout Mice
Insulin Resistance
Muscles
Wounds and Injuries
Skeletal Muscle
Glucose
Endocrinology
Secretory Pathway
Sarcoplasmic Reticulum
Glycolysis
Electron Transport Complex IV
Running
Regeneration
Mitochondria
Membrane Proteins
Proteins
Fibrosis
Phosphotransferases

Cite this

Tang, K., Pasqua, T., Biswas, A., Mahata, SK., Tang, J., Tang, A., ... Mahata, SK. (2017). Muscle injury, impaired muscle function and insulin resistance in Chromogranin a-knockout mice. Journal of Endocrinology, 232(2), 137-153. https://doi.org/10.1530/JOE-16-0370

Muscle injury, impaired muscle function and insulin resistance in Chromogranin a-knockout mice. / Tang, K; Pasqua, T; Biswas, A; Mahata, SK; Tang, J; Tang, A; Bandyopadhyay, GK; Sinha-Hikim, AP; Chil, NW; Webster, NJG; Corti, A; Mahata, SK.

In: Journal of Endocrinology, Vol. 232, No. 2, 2017, p. 137-153.

Research output: Contribution to journalArticle

Tang, K, Pasqua, T, Biswas, A, Mahata, SK, Tang, J, Tang, A, Bandyopadhyay, GK, Sinha-Hikim, AP, Chil, NW, Webster, NJG, Corti, A & Mahata, SK 2017, 'Muscle injury, impaired muscle function and insulin resistance in Chromogranin a-knockout mice', Journal of Endocrinology, vol. 232, no. 2, pp. 137-153. https://doi.org/10.1530/JOE-16-0370
Tang, K ; Pasqua, T ; Biswas, A ; Mahata, SK ; Tang, J ; Tang, A ; Bandyopadhyay, GK ; Sinha-Hikim, AP ; Chil, NW ; Webster, NJG ; Corti, A ; Mahata, SK. / Muscle injury, impaired muscle function and insulin resistance in Chromogranin a-knockout mice. In: Journal of Endocrinology. 2017 ; Vol. 232, No. 2. pp. 137-153.
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abstract = "Chromogranin A (CgA) is widely expressed in endocrine and neuroendocrine tissues as well as in the central nervous system. We observed CgA expression (mRNA and protein) in the gastrocnemius (GAS) muscle and found that performance of CgA-deficient Chga-KO mice in treadmill exercise was impaired. Supplementation with CgA in Chga-KO mice restored exercise ability suggesting a novel role for endogenous CgA in skeletal muscle function. Chga-KO mice display (i) lack of exercise-induced stimulation of pAKT, pTBC1D1 and phospho-p38 kinase signaling, (ii) loss of GAS muscle mass, (iii) extensive formation of tubular aggregates (TA), (iv) disorganized cristae architecture in mitochondria, (v) increased expression of the inflammatory cytokines Tnfα, Il6 and Ifn?, and fibrosis. The impaired maximum running speed and endurance in the treadmill exercise in Chga-KO mice correlated with decreased glucose uptake and glycolysis, defects in glucose oxidation and decreased mitochondrial cytochrome C oxidase activity. The lack of adaptation to endurance training correlated with the lack of stimulation of p38MAPK that is known to mediate the response to tissue damage. As CgA sorts proteins to the regulated secretory pathway, we speculate that lack of CgA could cause misfolding of membrane proteins inducing aggregation of sarcoplasmic reticulum (SR) membranes and formation of tubular aggregates that is observed in Chga-KO mice. In conclusion, CgA deficiency renders the muscle energy deficient, impairs performance in treadmill exercise and prevents regeneration after exercise-induced tissue damage. {\circledC} 2017 Society for Endocrinology.",
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AU - Tang, A

AU - Bandyopadhyay, GK

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AU - Corti, A

AU - Mahata, SK

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