Increased Autophagy as Cause of Muscle Atrophy after Spinal Cord Injury


The prevalence and incidence of spinal cord injury has remained stable from the year 2012 to 2013. The incidence stayed at 40 new cases per a million people in the United States. The prevalence increased slightly to an average of 273,000 people from around 200 000 people in 2012. Spinal cord injuries are accompanied by several complications one of which is skeletal muscle atrophy. This research has assessed the relationship between increased autophagy and spinal cord. It has also assessed the likelihood of increased autophagy as the cause of skeletal muscle atrophy. Results show that autophagy is as the cause of skeletal muscle atrophy. Excessive activation of autophagy causes muscle atrophy, but autophagy also regulates skeletal muscle growth. Recommendations propose that more research should be conducted to find out the relationship between SCI and autophagy, and the role of autophagy in skeletal muscle atrophy after SC

SpinalCode Injury (SCI)

Any trauma to the spinal cord anatomical structures causes spinal cord injury. There are 31 spinal cord column bones, also known as the vertebra. These are organized in a manner that an enclosed opening forms within and protects the spinal cord. Each vertebra has a body and an arch. These two form a vertebral foramen. Each vertebra is aligned on top of each other to form a spinal cord column (Fehlings & Vaccaro, 2012). It is within this column that the spinal cord is protected. The spinal cord is a package of nerves that pulls out from the brain downwards. However, it has peripheral branches. Any traumatic pressure on the spinal cord column can cause spinal cord injury. This affects the sensory, motor, and autonomic functions. People with spinal cord injuries normally remain with disabilities or deficits in their neurologic functions (Fehlings & Vaccaro, 2012).

The occurrence of SCI in the US is about 40 new cases per a million people (The National SCI Statistical Center, 2013). The CDC indicates that it is approximately 5 to 40 new cases per million people (CDC, 2010). It is estimated that an average of 273,000 people are living with SCI in the United States, that is, between 238, 000 to 332,000 (NSCIC, 2013). CDC approximates the number to be around 200, 000 (CDC, 2010).

Spinal cord complications depend on how severe the injury is, and the location of the injury. Common complications to spinal cord injury include pneumonia, spasticity, deep vein thrombosis, cardiovascular disease, skin breakdown, spinal cord pain, hyperthermia, Orthostatic Hypotension, and urinary tract infections. The complications depend on the sensory, autonomic, and motor functions affected in the injury. They also depend on the management of a patient’s condition (Fehlings & Vaccaro, 2012; Gall, Royal College of Physicians of London & Turner-Stokes, 2008).

Muscle Atrophy after Spinal Cord Injury

The spinal cord injury disrupts normal communication from the brain to the body organs. One of such affected areas can be the muscles. The spinal cord has five different sections, which perform different functions. There is the cervical section that contains neurons responsible for communication between the brain and the fingers, shoulders, neck muscles, wrist, diaphragm, and triceps. Any injury to these sections will affect the muscles of the body parts mentioned. Other sections of the spinal cord include; the thoracic section, lumbar, sacral, and coccygeal (Bradley, 2004).

After a spinal cord injury, muscle atrophy can occur in two ways. The first one is when the nerve that connects the muscle to the brain is damaged. This can occur through an injury, like the spinal cord injury. The second type is where the muscle tissue is wasted due to lack of physical activity. This normally occurs in bedridden patients, or those who cannot move due to their health status. Both types of muscle atrophy apply to spinal cord injury. The spinal cord is responsible for communicating messages to various parts of the body through neurons. When these are damaged, mostly in fall accidents, the neurons lose their normal functioning. Muscle atrophy therefore results. After a spinal injury, the patient will be forced to stay immobile before rehabilitation. The severity of the spinal cord injury also affects one’s physical activity. Due to the physical immobility caused after a spinal cord injury, the patient may suffer muscle atrophy (Bradley, 2004; Sandri, 2008).

Denervation of the muscles is the main cause of muscle atrophy. Muscle atrophy is characterised by results in reduced fibber diameter, protein content, fatigue resistance, and force production. There are different signalling paths that lead to muscle wasting. Some of them are dependent on the molecular triggers of muscle atrophy. In this case, it denervation, or disuse of the muscles (Jackman & Kandarian, 2004; Bonaldo & Sandri, 2013).

Muscle atrophy is also associated with increased connective and fat tissue. It is also characterised by increased disorganization of the internal ultra-structure of the fibers. The contractile materials become disorganized, and the fibers lose striation. Muscle atrophy caused by denervation is considered a natural response to the lack of activity in the muscles. It is a mechanism of reducing the load in muscles that are functionless (Boncompagni, 2012; Bonaldo & Sandri, 2013).


Increased Autophagy as a Cause of Skeletal Muscle Atrophy after Spinal Cord Injury


Autophagy is a system of degradation that takes the constituents of the cytoplasm to the lysosome (Mizushima, 2007; Nascimbeni, Fanin, Masiero, Angelini & Sandri, 2012). Glick, Barth and Macleod (2010) indicate that it is the process through which the cytosolic components are proteolytically degraded in the lysosome. Considering that this is a system of degradation, one can easily conclude that an increase in autophagy will cause skeletal muscle atrophy. A puzzling issue increased autophagy does not occur under normal circumstances. Increased autophagy has to have a relationship with spinal cord injury, for it to increase skeletal muscle atrophy.

There are two types of autophagy. There is autophagy that decreases during prolonged starvation, and there is autophagy that helps in the regulation of protein cytosolic components. The first one is known as induced autophagy that is triggered by starvation and is used to produce amino acids. In this type of macro-autophagy proteolysis is not sustained. The second one is basal autophagy, which is used to degrade cytosolic components to ensure a constitutive turnover (Mizushima, 2007). This discussion will not focus on induced autophagy because it is assumed that patients with spinal cord injury can eat healthily and avoid starvation.

It has already been established that skeletal muscle atrophy in spinal cord injury results from denervation and skeletal muscle physical inactivity. This section, therefore, will provide the molecular signalling pathways that induce muscle autophagy. It also explains how increased autophagy causes skeletal muscle atrophy.

Molecular Signalling Pathways That Induce Autophagy in Muscle Atrophy

The molecular signalling pathways that induce Atrophy are still not well understood. According to Sandri (2013), there are two molecular pathways; the autophagy-lysosome system and the ubiquitin-proteasome pathway. Both pathways are activated by FoxO transcription factors in atrophying of muscles. Below is a schematic representation of the process. Anything that activates muscle atrophy activates the transcription of FoxO3.



Autophagy                    Atrogin-1 and others


Lysosomal proteolysis                   Proteosaomal proteolysis


Muscle Atrophy

(Obtained from Lanham-New, Macdonald & Roche, 2011)

The Autophagy-Lysosome System

This pathway is activated by catabolic conditions such as in cases of ageing, cancer, sepsis, caloric restriction, denervation, fasting and disuse, among others. Research evidence has shown that autophagy is used for the provision of energy for sustained contraction of muscles and removal of organelles and proteins that have been damaged during exercise. In muscle atrophy, autophagy is induced through Bnip3 that remodels the mitochondria network which is used in the amplificatory loop for muscle atrophy (Sandri, 2013). The pathway is shown in figure 1.

Figure 1



Figure obtained from (Sandri, 2013).

There are several autophagy proteins involved in the regulation of autophagy process pathways. These include; Atg7, Atg5, Gate16, Atg12, Atg16, Gabarap, Atg10, LC3, and NAF-1 that down-regulate autophagosome biogenesis in muscle atrophy. There is also the beclin1/Vps34/Vps15 complex that regulates endosome trafficking and autophagosome biogenesis. It is also indicated that the complex ‘beclin1/Vps34/Vps15/Atg14L’, is necessary for autophagosome biogenesis. It is however not indicated how this complex forms (Sandri, 2013).

Even though there is a great advancement in research concerning the molecular signalling pathways, the functions of the main components of autophagy have not been determined. The pathway’s activities that lead to protein and organelle destruction are; membrane commitment, growth, autophagosome formation, autophagosome docking to lysosome, and the formation of autophagolysosome (Sandri, 2013). There are components linked to autophagy as described in figure 1, but their functions are yet to be well researched. There are also dotted lines indicating unknown mechanisms (Sandri, 2013).

The Ubiquitin-Proteasome Pathway

In this pathway there is a polypeptide chain co-factor, Ub that is linked to proteins that are supposed to be degraded. This process leads to the formation of a complex that acts as a marker for degradation. It can be recognized by the 26S proteasome, which then degrades them to small peptides. There are three main enzymatic components that carry out the ubiquition process. There is E1, which is a Ub activating enzyme. There are E2s that are the Ub conjugating proteins or carriers. E1 and E2s prepare the Ub for conjugation. The third enzyme, E3, catalyzes the relocation of stimulated Ubiquitin to it (Lecker, Goldberg & Mitch, 2006). This forms the ubiquition process. The protein, after ubiquition, is docked in the proteasome after which it will be degraded. The docking of a ubiquitinated protein for degradation only happens when the de-ubiquitinating enzymes do not remove the polyubiquitin chain. E3s that regulate muscle atrophy process and are also induced by the transcription of FoxO that have been identified are such as; Atrogin-1/MAFbx and MuRF1 (Sandri, 2013).


Figure 3.

Obtained from (Lecker, Goldberg & Mitch, 2006)

Autophagy in Muscle Atrophy

In muscle atrophy, research has established that there are genes that code for components responsible for independent regulation of the autophagy-lysosome machinery. These are atrogenes that regulate protein breakdown during atrophy, are the ones that activate autophagy. Autophagy is part of muscle atrophy process. The genes coding for GABARAP, LC3, Atg12, Bnip3, and Vps34, and other components of the autophagic machinery, are able to independently regulate autophagy-lysosome components and the ubiquitin-proteasome system, through the control of FoxO3 (Grumati & Bonaldo, 2012).

RUNX1 has also been found to be responsible for autophagy in skeletal muscles after a spinal cord injury. This explains how denervation induces autophagy that then leads to skeletal muscle atrophy. Under usual conditions, it is expected that the RUNX1 will be present in the muscles, and this controls the activation of autophagic flux. In denervated muscles, there is the lack of RUNX1, and this leads to excess autophagic flux which then contributes to muscle atrophy (Grumati & Bonaldo, 2012; Wang et al., 2005).

Another way of explaining how increased autophagy causes muscle atrophy is through the Akt/mTOR pathway. The mTOR pathway is engaged in the control of muscle size. In response to the muscle’s activities, this pathway can increase muscle size. The mTOR pathway interferes with protein destruction pathways. The Akt pathway also regulates protein degradation by inhibiting the translocation of FOXO. This activity then inhibits the activation of MuRF Atrogin-1 that are responsible protein degradation. During denervation, the mTOR regulator of autophagy is inhibited, which means autophagy increases (Lanham-New, Macdonald & Roche, 2011).








Muscle Atrophy Inhibitor (for example Insulin)




Non-Transcriptional                           FoxO3


Protein Synthesis         Autophagy                    Atrogin-1 and others


Lysosomal proteolysis                   Proteosaomal proteolysis


Muscle hypertrophy                                    Muscle Atrophy     (Obtained from

(Obtained from Lanham-New, Macdonald & Roche, 2011)

In this pathway, the critical factor in auophagy regulation in skeletal muscles is FoxO3. Its expression regulates autophagy protein genes such as Gabarap, LC3, Atg12, VPS34, and Bnip3 (Sandri, 2010).



Different studies however have shown that autophagy is essential for maintaining muscle mass. In Masiero and Sandri (2010), it was found that autophagy inhibition causes skeletal muscle atrophy (Masiero & Sandri, 2010). This is contrary to the information from Feeley (n.d), which leads one to conclude that increased autophagy can cause muscle atrophy. Masiero and Sandri (2010) indicate that autophagy is necessary for the removal of altered organelles and damaged proteins as well as for cellular survival. The authors however acknowledge that excessive activation of autophagy can lead to muscle loss (Sandri, 2010). Researchers have recently found that mice without the Atg7 gene were characterised by myofiber degeneration, muscle atrophy and weakness. It was also observed that inhibition of autophagy did not prevent muscle atrophy during fasting and denervation.


The Relationship between Autophagy and Spinal Cord Injury

Recent research shows that autophagy is increased in spinal cord injury cases. Ribas and others (2014) show in their study about axon deregulation that autophagy increases when one gets a spinal cord injury, and persists to degenerate axons. Since autophagy works to remove damaged cells, it was seen as a promising means through which therapeutic interventions can be developed (Ribas et al., 2014). After a spinal cord injury, there is increased expression of Beclin1. Kanno, Ozawa, Sekiguchi and Itoi (2009) showed that autophagy is activated by increased expression of Beclin 1. Beclin 1 is also responsible for the mediation of cell death mechanism at the site of injury after SCI (Kanno, Ozawa, Sekiguchi & Itoi, 2009).

Qin, Chen, Bin, Tiansi and Huilin (2014) observed the expression of autophagy proteins after a spinal cord injury. The results showed that LC3 (LC3-II/LC3-I) expressions were increased while the expression of Beclin -1 happened 12 hours after the injury. This confirms the role of Beclin-1 in the persistence of autophagy after spinal cord injury. It also shows the increased autophagy that happens after a spinal cord injury (Qin, Chen, Bin, Tiansi & Huilin, 2014).

LC3 is a marker of autophagy because it is a protein component of the autophagic pathway. After an activation of autophagy, LC3-II forms from the conversion of LC3-I. The component then binds to the autophagosomal membrane. Previous studies have confirmed that LC3 is expressed in a traumatic brain injury, explaining the activation of autophagy. This is the same theory that was used to discover autophagy activation in spinal cord injury. LC3 expression has been observed in oligodendrocytes, neurons, and astrocytes (Sekiguchi, Kanno, Ozawa & Itoi, n.d).

Evidence from literature sources shows that it is only the excessive activation of autophagy that causes skeletal muscle atrophy. This is because of the relationship between spinal cord injury and autophagy. After a spinal cord injury, more of autophagic proteins are expressed which means that the damaged cells have to be removed and protein constituents formed for new ones. This is according to the muscle homeostasis process. Autophagy is necessary for muscle growth. In spinal cord injury, however, there is persistent activation because of the existence of damaged neurons (Kanno, Ozawa, Sekiguchi & Itoi, 2009).


The relationship between autophagy and spinal cord injury is that an injury induces autophagy because of denervation. The information about autophagy and spinal cord injury is a bit confusing. It has been established that after an injury, LC3-1 and Beclin1 proteins are expressed signalling the activation of autophagy. There is information suggesting that Beclin1 is expressed 12 hours after a spinal cord injury. It is not determined if this expression persists for a long time or not. More literature search should identify the source of increased autophagy after spinal cord injury. Denervation is one of the causes, but more should be researched to find out if denervation leads to persistent activation of autophagy.

Another confusing part is in the role of autophagy in atrophy. Some research studies indicate that excessive autophagy causes skeletal muscle atrophy. These studies do not show the causes of excessive autophagy. Autophagy is revealed as a regulatory mechanism of the skeletal muscle growth and activities. It both degrades and forms protein for skeletal muscle growth.

Researches on specific genes responsible for autophagy are also a source of confusion. There is RUNX1 that regulates autophagy and is said to either increase or decrease muscle growth. There are three mechanisms through which RUNX1 regulates autophagy. RUNX1 may activate the genes that induce muscle activity to counter-balance muscle activity. This means that there are mechanisms in place to regulate autophagy when muscle activity is reduced. During spinal cord injury, the patient’s physical activity is greatly reduced, and some of them become immobile depending on the sections of the spinal cord that are injured. If autophagy can be regulated, then it means that in spinal cord injury, the regulation is impaired. More literature review should be conducted to find out why there is increased autophagy in spinal cord injury and if it persists all through the rehabilitation process. This gene is expressed during muscle atrophy. RUNX1 also regulates autophagy through activation of genes that compensate for muscle inactivity. The other means is through repression of genes that promote autophagy (Grumati & Bonaldo, 2012).

There is also this gene, Atg7 that is said to be responsible for autophagy. In a research investigating the effect of inhibiting autophagy, it was the expression of this gene that was inhibited. The results showed that the inhibition of autophagy does not reduce skeletal muscle atrophy. This shows that there are other factors causing skeletal muscle atrophy, and autophagy is not one of them (Masiero & Sandri, 2010).

Other genes that have been mentioned to be responsible for autophagy are; those that code for GABARAP, LC3, Atg12, Bnip3, and Vps34, and other components of the autophagic machinery. These genes are said to control autophagy-lysosome activities independently. This shows that there is more than Atg7 that are responsible for autophagy. It is important to establish the cause of increased autophagy after spinal cord injury. A review could also be conducted to organize the data about the relationship between spinal cord injury and autophagy.



This discussion has focussed on spinal cord injury, skeletal muscle atrophy in spinal cord injury and autophagy after a SCI. It first described spinal cord injury and its complications. From the third section in the discussion, it is clear that the main aim was to link autophagy to atrophy as a complication of spinal cord injury. It implies that increased autophagy could be the cause of skeletal muscle atrophy after SCI. This however needs clear proof since different literature sources indicated different relationships. There is increased expression of autophagy proteins after spinal cord injury. This clearly indicates that a SCI induces autophagy. The reason behind this could be denervation. It is then postulated that due to such denervation, autophagy is increased and atrophy results. The role of autophagy however shows that it either acts to increase atrophy or regulate muscle growth and size. Atrophy is also shown as a trigger of autophagy. Such relationships indicate that increased autophagy could be a cause of skeletal muscle atrophy, but more literature search is needed to identify the role of autophagy in skeletal muscle atrophy. More is also needed to establish the relationship between SCI and autophagy.








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