Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

Erin Stephenson, , , Quynh Tran, Binbin Lu, Matthew Peloquin, , Innocence Harvey, Kaleigh Fisher, Joan Han, Nathan Qi, Alan Saltiel and

bioRxiv 2019. This work is a preprint and is currently under review.

Abstract

The mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and age-associated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet- and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal muscle-specific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca2+ through SERCA2. Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan. These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.

Author Contributions

Erin Stephenson

Data Curation Formal Analysis Investigation Methodology Validation Visualization Writing - Original Draft Writing - Review and Editing

JeAnna Redd

Data Curation Formal Analysis Investigation Methodology Project Administration Writing - Review and Editing

Detrick Snyder

Formal Analysis Investigation Methodology Writing - Review and Editing

Quynh Tran

Data Curation Formal Analysis Investigation Methodology Resources Software Visualization Writing - Original Draft Writing - Review and Editing

Binbin Lu

Data Curation Formal Analysis Investigation Methodology Writing - Review and Editing

Matthew Peloquin

Data Curation Formal Analysis Investigation Methodology Project Administration Writing - Review and Editing

Molly Mulcahy

Formal Analysis Software Validation Visualization Writing - Review and Editing

Innocence Harvey

Investigation Methodology Writing - Review and Editing

Kaleigh Fisher

Data Curation Investigation Methodology Writing - Review and Editing

Joan Han

Conceptualization Resources Validation Writing - Review and Editing

Nathan Qi

Data Curation Formal Analysis Funding Acquisition Investigation Methodology Resources Writing - Review and Editing

Alan Saltiel

Conceptualization Data Curation Funding Acquisition Project Administration Resources Writing - Original Draft Writing - Review and Editing

Dave Bridges

Conceptualization Data Curation Formal Analysis Funding Acquisition Investigation Methodology Project Administration Resources Software Visualization Writing - Original Draft Writing - Review and Editing

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