Adenosine monophosphate activated protein kinase contributes to skeletal muscle health through the control of mitochondrial function

Abstract

Skeletal muscle is one of the largest organs in the body and the largest protein repository. Mitochondria are the main energy-producing organelles in cells and play an important role in skeletal muscle health and function. They participate in several biological processes related to skeletal muscle metabolism, growth, and regeneration. Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor and regulator of systemic energy balance. AMPK is involved in the control of energy metabolism by regulating many downstream targets. In this review, we propose that AMPK directly controls several facets of mitochondrial function, which in turn controls skeletal muscle metabolism and health. This review is divided into four parts. First, we summarize the properties of AMPK signal transduction and its upstream activators. Second, we discuss the role of mitochondria in myogenesis, muscle atrophy, regeneration post-injury of skeletal muscle cells. Third, we elaborate the effects of AMPK on mitochondrial biogenesis, fusion, fission and mitochondrial autophagy, and discuss how AMPK regulates the metabolism of skeletal muscle by regulating mitochondrial function. Finally, we discuss the effects of AMPK activators on muscle disease status. This review thus represents a foundation for understanding this biological process of mitochondrial dynamics regulated by AMPK in the metabolism of skeletal muscle. A better understanding of the role of AMPK on mitochondrial dynamic is essential to improve mitochondrial function, and hence promote skeletal muscle health and function.

Keywords: AMPK; mitochondria; muscle atrophy; muscle regeneration; skeletal muscle.

FIGURE 1

A schematic diagram of the pathways by which physiological activators activate adenosine monophosphate activated protein kinase (AMPK). The physiological activators are substances derived from the host’s own cells or tissues that activate AMPK. Physiological of AMPK include AMP/ADP, upstream kinases (LKB1, CaMKK2, TAK1, and AKT), VEGF and ROS. They are substances produced by the body that activate AMPK in different ways. AMPK is activated when the intracellular AMP/ADP ratio increases. As upstream kinases, LKB1, CaMKK2 and TAK1 can directly activate AMPK. When ROS is increased, excess ROS directly activates AMPK. He can also promote the interaction between STIM1 and Orai1 proximal to the plasma membrane, increasing calcium influx, activating CaMKK2 and subsequently AMPK. STIM1: stromal interaction molecule 1, Orai1: ORAI calcium release-activated calcium modulator 1, Akt: protein kinase B, VEGF: vascular endothelial growth factor, PLC: phospholipase C, LKB1: liver kinase B1, TAK1: TGF-beta-activated kinase 1.

FIGURE 2

A schematic diagram of the pathways by which pharmacological activators activate adenosine monophosphate activated protein kinase (AMPK). The pharmacological activators refer to substances that do not exist in the host itself but are synthesized artificially or exist in nature that can activate AMPK. (A) Indirect activations of AMPK mainly include canagliflozin, metformin and empagliflozin. These substances enter the body and indirectly activate AMPK by controlling molecules that control AMPK. (B) Direct activations of AMPK mainly include small molecules, dapagliflozin, plant-derived extracts, O304, sanguinarine, and AICAR. These substances enter the body and directly bind to AMPK to activate AMPK. DRP1: dynamin-related protein1, LKB1: liver kinase B1, ZMP: 5-aminoimidazole-4-carboxamide ribonucleoside monophosphate, C13: Compound 13, ETC-1002: bempedoic acid.

FIGURE 3

Mitochondria are extensively involved in the metabolic process of skeletal muscle cells. (A) Myogenesis: During the embryonic stage, stem cells form muscle progenitor cells under the intervention of regulatory factors and transcription factors, which are then activated and differentiate into myoblasts. Subsequently, the myoblasts exit the cell cycle and differentiate and fuse to form multinucleated myotubes. (B) Muscle regeneration: When muscle is injured, skeletal muscle heals itself through a programmed process. During degradation and inflammation, macrophages activate quiescent muscle stem cells (satellite cells) to differentiate into myoblasts, which then differentiate into muscle cells and fuse into myotubes to form muscle fibers and complete skeletal muscle repair. Pax3/Pax7: paired-box 3 and 7 transcription factors, Myod: myoblast determination protein 1, Myf5: myogenic factor 5, Myog: myogenin, Myf4: myogenin, MRF: myogenic regulatory factor, MEF2: myocyte enhancer factor 2.

FIGURE 4

Mitochondrial dysfunction promotes the skeletal muscle atrophy. When mitochondrial function is disrupted, ROS production increases, ATP synthesis decreases and other pathways lead to the activation of apoptosis pathway in muscle tissue, enhanced protein degradation, increased autophagy, muscle fiber breakdown, and eventually induce skeletal muscle atrophy. ROS: reactive oxygen species, AIF: apoptosis-inducing factor, FoxO3: forkhead box O 3.

FIGURE 5

Effects of AMPK on Mitochondrial Dynamics. AMPK promotes mitochondrial biogenesis, fusion, fission, and autophagy through different signaling pathways. FAO: fatty acid oxidation, PPAR: peroxisome proliferator-activated receptor, ERR: estrogen-related receptor, NRF1/2: nuclear respiratory factor 1/nuclear respiratory factor 2, PGC-1a: peroxisome proliferator-activated receptor gamma coactivator-1 alpha, MFN1/2: mitofusin 1/2, MFF: mitochondrial fission factor, DRP1: dynamin-related protein1, UQCRC2: ubiquinol-cytochrome c reductase core protein 2, Ulk1: autophagy activating kinase 1, FIS1: mitochondrial fission one protein, TFEB: transcriptional activity of transcription factor EB.