GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.

Autor:	Marcotte GR; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.; University of Iowa, Iowa City, Iowa, USA., Miller MJ; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.; University of Iowa, Iowa City, Iowa, USA., Kunz HE; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA., Ryan ZC; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA., Strub MD; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA., Vanderboom PM; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA., Heppelmann CJ; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA., Chau S; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA., Von Ruff ZD; University of Texas Medical Branch, Galveston, Texas, USA., Kilroe SP; University of Texas Medical Branch, Galveston, Texas, USA., McKeen AT; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.; University of Iowa, Iowa City, Iowa, USA., Dierdorff JM; University of Iowa, Iowa City, Iowa, USA., Stern JI; Department of Neurology and., Nath KA; Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA., Grueter CE; University of Iowa, Iowa City, Iowa, USA., Lira VA; University of Iowa, Iowa City, Iowa, USA., Judge AR; University of Florida, Gainesville, Florida, USA.; Emmyon, Inc., Rochester, Minnesota, USA., Rasmussen BB; University of Texas Medical Branch, Galveston, Texas, USA.; Emmyon, Inc., Rochester, Minnesota, USA.; University of Texas Health Science Center, San Antonio, Texas, USA., Nair KS; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA., Lanza IR; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA., Ebert SM; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Emmyon, Inc., Rochester, Minnesota, USA., Adams CM; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Emmyon, Inc., Rochester, Minnesota, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2023 Nov 22; Vol. 8 (22). Date of Electronic Publication: 2023 Nov 22.
DOI:	10.1172/jci.insight.171772
Abstrakt:	Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle-specific expression of growth arrest and DNA damage inducible α (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MAP kinase kinase kinase 4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.
Databáze:	MEDLINE
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