Mitochondrial dysfunction induces muscle atrophy during prolonged inactivity: A review of the causes and effects

Abstract

Prolonged skeletal muscle inactivity (e.g. limb immobilization, bed rest, mechanical ventilation, spinal cord injury, etc.) results in muscle atrophy that manifests into a decreased quality of life and in select patient populations, a higher risk of morbidity and mortality. Thus, understanding the processes that contribute to muscle atrophy during prolonged periods of muscle disuse is an important area of research. In this regard, mitochondrial dysfunction has been directly linked to the muscle wasting that occurs during extended periods of skeletal muscle inactivity. While the concept that mitochondrial dysfunction contributes to disuse muscle atrophy has been contemplated for nearly 50 years, the mechanisms connecting mitochondrial signaling events to skeletal muscle atrophy remained largely unexplained until recently. Indeed, emerging evidence reveals that mitochondrial dysfunction and the associated mitochondrial signaling events are a requirement for several forms of inactivity-induced skeletal muscle atrophy. Specifically, inactivity-induced alterations in skeletal muscle mitochondria phenotype and increased ROS emission, impaired Ca²⁺ handling, and release of mitochondria-specific proteolytic activators are established occurrences that promote fiber atrophy during prolonged periods of muscle inactivity. This review highlights the evidence that directly connects mitochondrial dysfunction and aberrant mitochondrial signaling with skeletal muscle atrophy and discusses the mechanisms linking these interconnected phenomena.

Keywords: Cell signaling; Disuse muscle atrophy; Mitochondrial dysfunction; Muscle wasting; Proteolysis; Reactive oxygen species.

Figure 1.. Prolonged muscle inactivity activates proteolytic pathways and decreases protein synthesis pathways.

Muscle inactivity activates four proteolytic systems that mediate protein degradation: 1) caspase-3; 2) calpain; 3) Autophagy; 4) and the ubiquitin proteasome system (UBS). Additionally, prolonged muscle inactivity results in the inhibition of the PI3K/Akt/mTOR pathway which mediates protein synthesis. See text for more details. FoxO, forkhead box O; MuRF-1, muscle ring finger protein-1; LC3, microtubule-associated proteins 1A/1B light chain 3b; Bnip3, BCL2 interacting protein 3; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mammalian/mechanistic target of rapamycin.

Figure 2.. Prolonged muscle inactivity induces mitochondrial dysfunction.

Mitochondria become dysfunctional during prolonged inactivity and demonstrate increased mitochondrial fission, decreased mitochondrial proteins, decreased mitochondrial protein import, and decreased cardiolipin. See text for more details. FIS1, mitochondrial fission 1; OPA1, optic atrophy 1; MFN, mitofusins; DRP1, dynamin related protein 1; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TFAM, mitochondrial transcription factor A.

Figure 3.. Dysfunctional mitochondria signal for proteolytic activation.

Prolonged inactivity induces mitochondrial dysfunction that activates proteolytic signaling. Increased intramitochondrial Ca²⁺, disruptions in cardiolipin, STAT3 translocation, and NADPH oxidase crosstalk increase ROS emissions. Dysfunctional mitochondria also release CytC and AIF that activate proteolytic pathways. Mitochondrial fission also results in disrupted energy production and activates FoxO via AMPK. See text for more details. DRP1, dynamin related protein 1; STAT3, signal transducer and activator of transcription 3; AMPK, AMP-activated protein kinase; CytC, cytochrome C; AIF, apoptosis inducing factor; FoxO, forkhead box O; mPTP, mitochondrial permeable transition pore. I, II, III, IV, denote complex I, complex II, complex III, and complex IV of the electron transport chain.