The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis
Objective: Skeletal muscle insulin signaling is a major determinant of muscle growth and glucose homeostasis. Protein kinase B/Akt plays a prominent role in mediating many of the metabolic effects of insulin. Mice and humans harboring systemic loss-of-function mutations in Akt2, the most abundant Ak...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-10-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877819305861 |
| _version_ | 1811319892300791808 |
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| author | N. Jaiswal M.G. Gavin W.J. Quinn, III T.S. Luongo R.G. Gelfer J.A. Baur P.M. Titchenell |
| author_facet | N. Jaiswal M.G. Gavin W.J. Quinn, III T.S. Luongo R.G. Gelfer J.A. Baur P.M. Titchenell |
| author_sort | N. Jaiswal |
| collection | DOAJ |
| description | Objective: Skeletal muscle insulin signaling is a major determinant of muscle growth and glucose homeostasis. Protein kinase B/Akt plays a prominent role in mediating many of the metabolic effects of insulin. Mice and humans harboring systemic loss-of-function mutations in Akt2, the most abundant Akt isoform in metabolic tissues, are glucose intolerant and insulin resistant. Since the skeletal muscle accounts for a significant amount of postprandial glucose disposal, a popular hypothesis in the diabetes field suggests that a reduction in Akt, specifically in skeletal muscle, leads to systemic glucose intolerance and insulin resistance. Despite this common belief, the specific role of skeletal muscle Akt in muscle growth and insulin sensitivity remains undefined. Methods: We generated multiple mouse models of skeletal muscle Akt deficiency to evaluate the role of muscle Akt signaling in vivo. The effects of these genetic perturbations on muscle mass, glucose homeostasis and insulin sensitivity were assessed using both in vivo and ex vivo assays. Results: Surprisingly, mice lacking Akt2 alone in skeletal muscle displayed normal skeletal muscle insulin signaling, glucose tolerance, and insulin sensitivity despite a dramatic reduction in phosphorylated Akt. In contrast, deletion of both Akt isoforms (M-AktDKO) prevented downstream signaling and resulted in muscle atrophy. Despite the absence of Akt signaling, in vivo and ex vivo insulin-stimulated glucose uptake were normal in M-AktDKO mice. Similar effects on insulin sensitivity were observed in mice with prolonged deletion (4 weeks) of both skeletal muscle Akt isoforms selectively in adulthood. Conversely, short term deletion (2 weeks) of skeletal muscle specific Akt in adult muscles impaired insulin tolerance paralleling the effect observed by acute pharmacological inhibition of Akt in vitro. Mechanistically, chronic ablation of Akt induced mitochondrial dysfunction and activation of AMPK, which was required for insulin-stimulated glucose uptake in the absence of Akt. Conclusions: Together, these data indicate that chronic reduction in Akt activity alone in skeletal muscle is not sufficient to induce insulin resistance or prevent glucose uptake in all conditions. Therefore, since insulin-stimulated glucose disposal in skeletal muscle is markedly impaired in insulin-resistant states, we hypothesize that alterations in signaling molecules in addition to skeletal muscle Akt are necessary to perturb glucose tolerance and insulin sensitivity in vivo. Keywords: Insulin signaling, Glucose uptake, Muscle metabolism, Akt, Glucose homeostasis, Mitochondria dysfunction |
| first_indexed | 2024-04-13T12:50:09Z |
| format | Article |
| id | doaj.art-4f01c8d4ca0f437ea68c831458c44749 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-13T12:50:09Z |
| publishDate | 2019-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-4f01c8d4ca0f437ea68c831458c447492022-12-22T02:46:14ZengElsevierMolecular Metabolism2212-87782019-10-0128113The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasisN. Jaiswal0M.G. Gavin1W.J. Quinn, III2T.S. Luongo3R.G. Gelfer4J.A. Baur5P.M. Titchenell6Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAInstitute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAInstitute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAInstitute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAInstitute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAInstitute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Physiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAInstitute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Physiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Corresponding author. 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.Objective: Skeletal muscle insulin signaling is a major determinant of muscle growth and glucose homeostasis. Protein kinase B/Akt plays a prominent role in mediating many of the metabolic effects of insulin. Mice and humans harboring systemic loss-of-function mutations in Akt2, the most abundant Akt isoform in metabolic tissues, are glucose intolerant and insulin resistant. Since the skeletal muscle accounts for a significant amount of postprandial glucose disposal, a popular hypothesis in the diabetes field suggests that a reduction in Akt, specifically in skeletal muscle, leads to systemic glucose intolerance and insulin resistance. Despite this common belief, the specific role of skeletal muscle Akt in muscle growth and insulin sensitivity remains undefined. Methods: We generated multiple mouse models of skeletal muscle Akt deficiency to evaluate the role of muscle Akt signaling in vivo. The effects of these genetic perturbations on muscle mass, glucose homeostasis and insulin sensitivity were assessed using both in vivo and ex vivo assays. Results: Surprisingly, mice lacking Akt2 alone in skeletal muscle displayed normal skeletal muscle insulin signaling, glucose tolerance, and insulin sensitivity despite a dramatic reduction in phosphorylated Akt. In contrast, deletion of both Akt isoforms (M-AktDKO) prevented downstream signaling and resulted in muscle atrophy. Despite the absence of Akt signaling, in vivo and ex vivo insulin-stimulated glucose uptake were normal in M-AktDKO mice. Similar effects on insulin sensitivity were observed in mice with prolonged deletion (4 weeks) of both skeletal muscle Akt isoforms selectively in adulthood. Conversely, short term deletion (2 weeks) of skeletal muscle specific Akt in adult muscles impaired insulin tolerance paralleling the effect observed by acute pharmacological inhibition of Akt in vitro. Mechanistically, chronic ablation of Akt induced mitochondrial dysfunction and activation of AMPK, which was required for insulin-stimulated glucose uptake in the absence of Akt. Conclusions: Together, these data indicate that chronic reduction in Akt activity alone in skeletal muscle is not sufficient to induce insulin resistance or prevent glucose uptake in all conditions. Therefore, since insulin-stimulated glucose disposal in skeletal muscle is markedly impaired in insulin-resistant states, we hypothesize that alterations in signaling molecules in addition to skeletal muscle Akt are necessary to perturb glucose tolerance and insulin sensitivity in vivo. Keywords: Insulin signaling, Glucose uptake, Muscle metabolism, Akt, Glucose homeostasis, Mitochondria dysfunctionhttp://www.sciencedirect.com/science/article/pii/S2212877819305861 |
| spellingShingle | N. Jaiswal M.G. Gavin W.J. Quinn, III T.S. Luongo R.G. Gelfer J.A. Baur P.M. Titchenell The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis Molecular Metabolism |
| title | The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis |
| title_full | The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis |
| title_fullStr | The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis |
| title_full_unstemmed | The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis |
| title_short | The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis |
| title_sort | role of skeletal muscle akt in the regulation of muscle mass and glucose homeostasis |
| url | http://www.sciencedirect.com/science/article/pii/S2212877819305861 |
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