Date of Award

2020

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Zijian Xie, Committee Chairperson

Second Advisor

Dr. Sandrine Pierre, Committee Co-Chairperson

Third Advisor

Dr. Nalini Santanam

Fourth Advisor

Dr.Joseph Shapiro

Fifth Advisor

Dr. Judith Heiny

Abstract

Skeletal muscle comprises approximately 30% of total body mass, and loss of muscle mass and dysfunctional muscle metabolism are implicated in multiple disease states, including type 2 diabetes, heart failure, and septic shock. As such, understanding the mechanisms of skeletal muscle growth and atrophy, including pharmaceutical targets that may prove safe and effective, is therefore an important goal of current research on skeletal muscle physiology. One potential target in skeletal muscle development and function that has not been fully explored is the Na/KATPase (NKA), especially the α1 isoform. This isoform has a unique signaling function that has previously been shown to regulate growth, metabolism, and organogenesis and comprises only 10% of the total NKA in skeletal muscle. We therefore investigated the role of this signaling isoform in skeletal muscle. To accomplish this, we utilized a global NKA α1 haplodeficient mouse (α1+/-). The oxidative soleus muscles of skα1+/- were 10% smaller than controls, while the glycolytic extensor digitorum longus mass was unchanged. This prompted us to analyze the metabolism of cells lacking NKA α1, which revealed that the α1 isoform is necessary for metabolic reserve and flexibility. A second mouse model was generated with a skeletal musclespecific ablation of NKA α1. These mice had a 35% reduction in skeletal muscle mass and a switch from oxidative to glycolytic fibers. Paradoxically, these mice were protected from dietinduced metabolic dysfunction including diet-induced insulin resistance. This provided the first genetic in vivo model of α1 signaling as a major regulator of metabolism and led to the hypothesis that the evolution of the Src binding sites in α1 in mammals may be linked to the development of increased metabolic reserve associated with the evolution of endothermy. These findings together confirm a vital role of NKA α1 in skeletal muscle development and metabolism, and link the evolution of endothermy to the evolution of the NKA α1 Src binding sites.

Subject(s)

Muscles -- Research.

Musculoskeletal system -- Research.

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