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The Role of Endoplasmic Reticulum Associated Degradation in Skeletal Muscle Growth and Metabolism.

紀錄類型:	書目-語言資料,手稿 : Monograph/item
正題名/作者:	The Role of Endoplasmic Reticulum Associated Degradation in Skeletal Muscle Growth and Metabolism./
作者:	Abdon, Benedict Trinidad.
面頁冊數:	1 online resource (163 pages)
附註:	Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
Contained By:	Dissertations Abstracts International85-03B.
標題:	Physiology. -
電子資源:	click for full text (PQDT)
ISBN:	9798380373883

The Role of Endoplasmic Reticulum Associated Degradation in Skeletal Muscle Growth and Metabolism.
Abdon, Benedict Trinidad.

The Role of Endoplasmic Reticulum Associated Degradation in Skeletal Muscle Growth and Metabolism. - 1 online resource (163 pages)

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

Thesis (Ph.D.)--University of Michigan, 2023.

Includes bibliographical references

The endoplasmic reticulum (ER) is a specialized organelle optimized for the synthesis and maturation of transmembrane and secretory proteins. Under cellular or environmental stress, proteins in the ER may misfold or aggregate, jeopardizing cellular function. However, numerous ER quality control pathways are present to maintain protein homeostasis (proteostasis). Among these is endoplasmic reticulum-associated degradation (ERAD), a process that targets misfolded ER proteins for proteasomal degradation, thereby preserving cellular proteostasis. Multiple ERAD complexes have been identified to provide specificity for various protein substrates, of which, the Suppressor/enhancer of Lin-12 Like-HMG-coA reductase degradation (SEL1L-HRD1) ERAD complex is the best characterized. Despite its critical function, the physiological role of ERAD and the SEL1L-HRD1 complex in skeletal muscle, a tissue reliant on optimal proteostasis for growth and health, is largely unexplored. This dissertation begins to fill this knowledge gap. Transgenic mice with muscle-specific deletion of SEL1L display impaired muscle growth early in life that triggers a whole-body metabolic reprogramming in adult mice. Specifically, the phenotype of these mice includes stunted body growth, reduced lean mass, enhanced insulin sensitivity, resistance to diet induced obesity, and beiging of white adipose tissue. These metabolic effects are mediated, in part, by the release of the hormone fibroblast growth factor-21 (FGF21) from the muscle which we found to directly initiate UCP1 mediated beiging of adipose tissue and contribute to the impaired body growth of mice lacking muscle-specific SEL1L. Molecularly, we provide evidence that loss of SEL1L results in altered proteostatic and energy pathways within the muscle, including the enhancement of the unfolded protein response, autophagy, and impaired mitochondrial function. We further showed that SEL1L in the ER is required to maintain mitochondrial dynamics, networking, and morphology in skeletal muscle. These mitochondrial phenotypes impaired mitochondrial respiration. Together, this work shows for the first time that SEL1L-HRD1 ERAD plays a critical role in promoting postnatal muscle hypertrophy and preserving mitochondrial function in skeletal muscle. The findings underscore the importance of the integrated relationship between ER proteostasis and mitochondria in skeletal muscle, which is indispensable for proper muscle growth and the maintenance of systemic energy metabolism.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798380373883Subjects--Topical Terms:

673386
Physiology.
Subjects--Index Terms:

Muscle physiologyIndex Terms--Genre/Form:

554714
Electronic books.

The Role of Endoplasmic Reticulum Associated Degradation in Skeletal Muscle Growth and Metabolism.
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520 $a The endoplasmic reticulum (ER) is a specialized organelle optimized for the synthesis and maturation of transmembrane and secretory proteins. Under cellular or environmental stress, proteins in the ER may misfold or aggregate, jeopardizing cellular function. However, numerous ER quality control pathways are present to maintain protein homeostasis (proteostasis). Among these is endoplasmic reticulum-associated degradation (ERAD), a process that targets misfolded ER proteins for proteasomal degradation, thereby preserving cellular proteostasis. Multiple ERAD complexes have been identified to provide specificity for various protein substrates, of which, the Suppressor/enhancer of Lin-12 Like-HMG-coA reductase degradation (SEL1L-HRD1) ERAD complex is the best characterized. Despite its critical function, the physiological role of ERAD and the SEL1L-HRD1 complex in skeletal muscle, a tissue reliant on optimal proteostasis for growth and health, is largely unexplored. This dissertation begins to fill this knowledge gap. Transgenic mice with muscle-specific deletion of SEL1L display impaired muscle growth early in life that triggers a whole-body metabolic reprogramming in adult mice. Specifically, the phenotype of these mice includes stunted body growth, reduced lean mass, enhanced insulin sensitivity, resistance to diet induced obesity, and beiging of white adipose tissue. These metabolic effects are mediated, in part, by the release of the hormone fibroblast growth factor-21 (FGF21) from the muscle which we found to directly initiate UCP1 mediated beiging of adipose tissue and contribute to the impaired body growth of mice lacking muscle-specific SEL1L. Molecularly, we provide evidence that loss of SEL1L results in altered proteostatic and energy pathways within the muscle, including the enhancement of the unfolded protein response, autophagy, and impaired mitochondrial function. We further showed that SEL1L in the ER is required to maintain mitochondrial dynamics, networking, and morphology in skeletal muscle. These mitochondrial phenotypes impaired mitochondrial respiration. Together, this work shows for the first time that SEL1L-HRD1 ERAD plays a critical role in promoting postnatal muscle hypertrophy and preserving mitochondrial function in skeletal muscle. The findings underscore the importance of the integrated relationship between ER proteostasis and mitochondria in skeletal muscle, which is indispensable for proper muscle growth and the maintenance of systemic energy metabolism.
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