Effects of exercise on obesity-induced mitochondrial dysfunction in skeletal muscle

Abstract

Obesity is known to induce inhibition of glucose uptake, reduction of lipid metabolism, and progressive loss of skeletal muscle function, which are all associated with mitochondrial dysfunction in skeletal muscle. Mitochondria are dynamic organelles that regulate cellular metabolism and bioenergetics, including ATP production via oxidative phosphorylation. Due to these critical roles of mitochondria, mitochondrial dysfunction results in various diseases such as obesity and type 2 diabetes. Obesity is associated with impairment of mitochondrial function (e.g., decrease in O₂ respiration and increase in oxidative stress) in skeletal muscle. The balance between mitochondrial fusion and fission is critical to maintain mitochondrial homeostasis in skeletal muscle. Obesity impairs mitochondrial dynamics, leading to an unbalance between fusion and fission by favorably shifting fission or reducing fusion proteins. Mitophagy is the catabolic process of damaged or unnecessary mitochondria. Obesity reduces mitochondrial biogenesis in skeletal muscle and increases accumulation of dysfunctional cellular organelles, suggesting that mitophagy does not work properly in obesity. Mitochondrial dysfunction and oxidative stress are reported to trigger apoptosis, and mitochondrial apoptosis is induced by obesity in skeletal muscle. It is well known that exercise is the most effective intervention to protect against obesity. Although the cellular and molecular mechanisms by which exercise protects against obesity-induced mitochondrial dysfunction in skeletal muscle are not clearly elucidated, exercise training attenuates mitochondrial dysfunction, allows mitochondria to maintain the balance between mitochondrial dynamics and mitophagy, and reduces apoptotic signaling in obese skeletal muscle.

Keywords: Exercise; Mitochondria; Obesity; Skeletal Muscle.

Fig. 1. Effects of obesity and exercise training on mitochondrial dysfunction.

Exercise training protects against obesity-induced mitochondrial dysfunction (e.g., O₂ respiration, ATP production, ROS emission, β-oxidation, markers of TCA cycle, mtDNA mutation) in skeletal muscle. TCA cycle, tricarboxylic acid cycle; ROS, reactive oxygen species; ADP, adenosine diphosphate; ATP, adenosine triphosphate.

Fig. 2. Schematic overview of mitochondrial dynamics impaired by obesity and adaptation to exercise training.

Obesity impairs mitochondrial membrane potential and triggers oxidative stress, resulting in imbalance of mitochondrial fusion and fission and elevation of fission proteins. However, exercise training allows mitochondria to maintain the balance between fusion and fission by up-regulating fusion proteins and down-regulating fission proteins. ↓, decrease; ↑, increase; =, no change.

Fig. 3. Mitophagy pathways, including (i) Parkin-dependent pathway and (ii) Parkin-independent pathway.

In the Parkin-dependent pathway, Pink1 recruits Parkin from the cytoplasm to mitochondrial outer membrane. After Parkin has been recruited to mitochondria, activated Parkin ubiquitinates proteins in the mitochondrial outer membrane such as MFN and VDAC (Voltage-Dependent Anion Channel) to facilitate mitophagy. Parkinmediated ubiquitination recruits autophagy adapter proteins such as p62 and optineurin, and these proteins interact with LC3. LC3 participates in formation of an autophagosome, which is fated for lysosomal destruction to clear out damaged mitochondrion. The second pathway called the Parkin-independent pathway is generated without Parkin protein. When mitochondria are damaged, several autophagy receptor proteins such as BNIP3, NIX, and FUNDC1 are recruited to regulate mitophagy. These autophagy receptors directly interact with LC3 to form an autophagosome and degrade damaged mitochondria in the lysosome. ↓, decrease; ↑, increase; PARL, presenilins-associated-rhomboid-like; VDAC, Voltage-Dependent Anion Channel; MFN, mitofusin; UB, ubiquitination; BNIP3, bcl-2/adenovirus E1B interacting protein 3; NIX, nip3-like protein x; FUNDC1, fun14 domain-containing protein 1.

Fig. 4. Potential mechanisms of obesity-induced impairment in mitophagy.

Obesity may induce defective or excessive mitophagy. Specifically, excessive mitophagy induces cellular/mitochondrial stress and causes skeletal muscle loss through increased protein degradation, whereas deficiency of mitophagy leads to accumulation of dysfunctional mitochondria in skeletal muscle.

Fig. 5. Schematic overview of two obesity-induced apoptotic signaling pathways, including caspase-dependent pathway and caspase-independent pathway.

As a caspase-dependent pathway, obesity increases the Bax/Bcl-2 ratio and facilitates mPTP opening. Upon mPTP opening, cytochrome c is released from mitochondria to the cytosol. Released cytochrome c activates caspase-9 and cleaves caspase-3. Cleaved caspase-3 induces DNA fragmentation, leading to apoptosis. The relationship between obesity and the caspase-independent pathway has been rarely studied. ↓, decrease; ↑, increase; mPTP, mitochondrial permeability transition pore; AIF, apoptosis-inducing factor; Endo G, endonuclease G.