I read that lack of action leads to muscle atrophy , I experienced same when I had a cast for hand fracture. So how far this atrophy go, who decides minimum size of muscle due to lack of activity, for example in coma patients. Which part to brain or body signals muscle atrophy and upto what limit it should go?
Skeletal Muscle Atrophy
Skeletal muscle atrophy occurs in response to a variety of pathophysiological stimuli, and contributes to profound losses of muscle mass and whole body strength ( Jackman and Kandarian, 2004 ). Among the stimuli that trigger the loss of muscle mass is cachexia. Cachetic muscle wasting is a form of pathophysiological wasting that often accompanies chronic diseases such as cancer ( Argiles et al., 2009 ) and chronic heart failure, and more acute conditions such as sepsis ( Cai et al., 2004 Hasselgren et al., 2005 ). Although patients affected by these conditions may suffer from some level of disuse wasting as a consequence of inactivity due to their disease, cachectic wasting is believed to predominately result from increased levels of systemic circulating factors such as inflammatory cytokines that are elevated by the host immune system in response to the disease ( Tisdale, 1997 ). In addition to immune-derived factors, tumor-secreted factors in cancer patients, and blood-borne lipopolysaccharide from the bacterial infection in septic patients, are also implicated in the pathogenesis of muscle wasting ( Tisdale, 1997 ). Therefore, although there are multiple distinct triggers of muscle wasting, in the clinical population, muscle wasting is often a complex condition that may involve numerous underlying triggers.
Importantly, the loss of muscle mass not only effects muscle strength and function, it also increases the risk for metabolic disorders such as diabetes, contributes to prolonged and/or impaired recovery following hospital stays, and in the most severe cases, contributes to increased mortality ( Kersey and Gajl-Peczalska, 1975 Tisdale, 1997 ). Therefore, improving our understanding of how skeletal muscle atrophy is regulated is clinically significant for not only combating or alleviating the muscle atrophy itself, but enhancing patient health and survival. Initial muscle dysfunction can lead to reduced activity and loss of muscle mass. The muscle weakness can further increase the risk of bone fractures, already high in this patient population, by unloading bone and causing increased bone destruction. Muscle weakness also increases the risk of falls, thus muscle loss sets up a vicious cycle of continued musculoskeletal degradation.
There are several systems that have been implicated in the protein degradation of skeletal muscle. The two that have received the most attention, the calpain and ubiquitin-proteasome system (UPS), are most likely the primary ways that myofibrillar proteins are degraded while the caspase system (involved with cell apoptosis and autophagy) is partially responsible for normal cell turn-over. These four systems work in conjunction with each other to negatively regulate muscle mass in various physiological conditions. The following will discuss these systems in further detail.
What to know about muscle atrophy
The term muscle atrophy refers to the loss of muscle tissue. Atrophied muscles appear smaller than normal. Lack of physical activity due to an injury or illness, poor nutrition, genetics, and certain medical conditions can all contribute to muscle atrophy.
Muscle atrophy can occur after long periods of inactivity. If a muscle does not get any use, the body will eventually break it down to conserve energy.
Muscle atrophy that develops due to inactivity can occur if a person remains immobile while they recover from an illness or injury. Getting regular exercise and trying physical therapy may reverse this form of muscle atrophy.
People can treat muscle atrophy by making certain lifestyle changes, trying physical therapy, or undergoing surgery.
In this article, we look at some other causes, symptoms, and treatments of muscle atrophy.
Many factors can cause muscle atrophy, including:
Share on Pinterest Muscle atrophy has numerous potential causes.
Poor nutrition can give rise to numerous health conditions, including muscle atrophy.
Specifically, the International Osteoporosis Foundation warn that diets low in lean protein, fruits, and vegetables can lead to reductions in muscle mass.
Malnutrition-related muscle atrophy may develop as a result of medical conditions that impair the body’s ability to absorb nutrients, such as:
Cachexia is a complex metabolic condition that causes extreme weight loss and muscle atrophy. Cachexia can develop as a symptom of another underlying condition, such as cancer, HIV, or multiple sclerosis (MS).
People who have cachexia may experience a significant loss of appetite or unintentional weight loss despite consuming a large number of calories.
As a person gets older, their body produces fewer proteins that promote muscle growth. This reduction of available protein causes the muscle cells to shrink, resulting in a condition called sarcopenia.
According to a Food and Drug Administration (FDA) report, sarcopenia affects up to a third of people ages 60 and above.
In addition to reduced muscle mass, sarcopenia can cause the following symptoms:
A loss of muscle mass may be an inevitable result of the natural aging process. However, it can increase the risk of injuries and negatively impact a person’s overall quality of life.
Spinal muscular atrophy (SMA) is a genetic disorder that causes a loss of motor nerve cells and muscle atrophy.
There are several different types of SMA that fall into the following categories:
- SMA linked to chromosome 5: These types of SMA occur due to a mutation in the SMN1 genes on chromosome 5. The mutations lead to a deficiency of the survival motor neuron protein. SMA typically develops in childhood but can develop at any point in life.
- SMA not linked to chromosome 5
Muscular dystrophy refers to a group of progressive conditions that cause loss of muscle mass and weakness.
Muscular dystrophy occurs when one of the genes involved in protein production mutates. A person can inherit genetic mutations, but many occur naturally as the embryo develops.
Share on Pinterest Atrophied muscles are smaller than healthy muscles.
Image credit: OpenStax, 2016.
Diseases and chronic conditions that can contribute to muscle atrophy include:
- Amyotrophic lateral sclerosis (ALS): Also called Lou Gehrig’s disease, ALS includes several types that damage the motor nerve cells that control the muscles.
- MS: This chronic condition occurs when the body’s immune system attacks the central nervous system, causing harmful inflammation in the nerve fibers.
- Arthritis: Arthritis refers to inflammation of the joints that causes pain and stiffness. Arthritis can severely limit a person’s mobility, which could lead to muscle disuse and atrophy.
- Myositis: The term myositis refers to inflammation of the muscles. This condition causes muscle weakness and pain. People can develop myositis after a viral infection or as a side effect of an autoimmune condition. : This infectious disease attacks the nervous system. It causes flu-like symptoms and can result in permanent paralysis.
An injury or condition can damage the nerves that control the muscles, resulting in a condition called neurogenic muscle atrophy.
When this develops, the muscles stop contracting because they no longer receive signals from the nerve.
The symptoms of muscle atrophy vary widely depending on the cause and severity of muscle loss.
In addition to reduced muscle mass, symptoms of muscle atrophy include:
- having one arm or leg that is noticeably smaller than the others
- experiencing weakness in one limb or generally
- having difficulty balancing
- remaining inactive for an extended period
Treatments for muscle atrophy vary depending on the degree of muscle loss and the presence of any underlying medical conditions.
Treating the underlying condition causing the muscle atrophy may help slow down the progression of the muscle loss.
Treatments for muscle atrophy include:
Physical therapy involves performing specific stretches and exercises with the aim of preventing immobility. Physical therapy offers the following benefits to people who have muscle atrophy:
- preventing immobility
- increasing muscle strength
- improving circulation
- reducing spasticity, which causes continuous muscle contraction
Functional electric stimulation
Functional electrical stimulation (FES) is another effective treatment for muscle atrophy. It involves the use of electrical impulses to stimulate muscle contraction in affected muscles.
During FES, a trained technician attaches electrodes to an atrophied limb. The electrodes transmit an electrical current, which triggers movement in the limb.
Focused ultrasound therapy
This technique delivers beams of ultrasound energy to specific areas in the body. The beams stimulate contractions in atrophied muscle tissue.
This novel technology is in the development phase and has not yet entered the clinical trial phase.
Surgical procedures may improve muscle function in people whose muscle atrophy is related to neurological conditions, injuries, or malnutrition.
Muscle atrophy is a physiological consequence of aging (i.e., age-related sarcopenia), defined as the presence of both low muscle mass and low muscle function (strength or performance) , but it may also result from prolonged periods of rest or a sedentary lifestyle. Moreover, muscle atrophy represents a clinical feature of cachexia, a multifactorial syndrome implying reduced life expectancy and accompanying many illnesses like chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), cancer, HIV, sepsis, immune disorders, and dystrophies .
A reduced cross-sectional area of myofibers with subsequent impaired strength is the main characteristic of muscle atrophy , mirroring a consistent depletion of contractile proteins. Muscle atrophy is also frequently characterized by a switch of the fiber-type composition. For instance, while the loss of contractile proteins predominantly affects the type II fast fibers during aging or cancer cachexia , giving rise to a higher proportion of slow versus fast fibers , an increase in type IIX fiber proportions at the expense of either type I or type IIA muscle fibers has been observed in CHF [5𠄷], suggesting that different pathophysiological cues may differently affect the fiber-type muscular pattern. Besides the loss of muscle mass, inherent deficits in the “quality” of skeletal muscle have been demonstrated. For instance, in symptomatic CHF patients, quadriceps muscle strength is reduced compared to controls, even after correction for reduced circumferential area . Equally important, however, are the prognostic implications of cachexia and muscle loss. Anker et al.  provided strong evidence that the identification of a heart failure patient as being cachectic significantly increased the risk of dying, even after correction for age, gender, disease severity, and treatment allocation.
Until recently, the lack of a clear definition for cachexia has hampered structured research as well as the development of treatment targets. Therefore, in order to allow timely clinical recognition, objective criteria to define cachexia have become mandatory. According to the last consensus criteria, the condition sine qua non to define cachexia is weight loss greater than 5 % or weight loss greater than 2 % in individuals already showing depletion according to current body weight and height (BMI 㰠) or skeletal muscle mass . However, the assessment for classification and clinical management of cachectic patients should include additional domains such as anorexia or reduced food intake, catabolic drive, muscle mass, and strength as well as functional and psychosocial impairment.
Altogether, these observations clearly indicate that different, somewhat apparently unrelated mechanisms may synergistically cooperate to trigger the impairment of body's performance through loss of bulk muscle, thereby inducing critical and often fatal health complications.
The autophagy-lysosome system
Autophagy plays a crucial role in the turnover of cell components both in constitutive conditions and in response to various stimuli, such as cellular stress, nutrient deprivation, amino acid starvation and cytokines (Mizushima et al., 2008). Three different mechanisms have been described in mammals for the delivery of the autophagic cargo to lysosomes: macroautophagy, chaperone-mediated autophagy (CMA) and microautophagy ( Fig. 2 ). Thus far, most data on the role of the autophagic process in muscle are related to macroautophagy. Although it is still unknown whether microautophagy occurs in skeletal muscle, some findings indicate that microautophagy can participate in glycogen uptake into lysosomes when macroautophagy is blocked (Raben et al., 2008 Takikita et al., 2010). CMA has raised interest owing to its potential role in aging, neurodegenerative disorders and lysosomal storage diseases (Kon and Cuervo, 2010) however, whether it has roles in muscle homeostasis or atrophy is still largely unknown. In a study analyzing the contribution of CMA to protein breakdown in various organs of fasted rats, it was speculated that increased proteolysis in the liver and heart of fasted animals involves activation of CMA, but that this does not occur in skeletal muscles (Wing et al., 1991). The involvement of CMA in muscle homeostasis is an issue that needs to be addressed in detail in the coming years.
Autophagy was first described many years ago, but its involvement in muscle protein breakdown during atrophy was not recognized for a long time. Early evidence showed that lysosomal degradation contributes to protein breakdown in denervated muscle (Furuno et al., 1990 Schiaffino and Hanzlíková, 1972). Moreover, cathepsin L, a lysosomal protease, was shown to be upregulated during muscle atrophy (Deval et al., 2001). The development of molecular and imaging tools to follow autophagosome formation has greatly improved the characterization of autophagy in normal and atrophying muscles (Klionsky et al., 2008). In fact, analysis of different organs revealed that skeletal muscle is one of the tissues with the highest rates of vesicle formation during fasting. Interestingly, fast glycolytic muscles display a higher content of autophagosomes than slow β-oxidative muscles (Mizushima et al., 2004). It is now known that myofiber atrophy induced by in vivo overexpression of constitutively active FoxO3 requires autophagy, and siRNA-mediated knockdown of LC3 (a protein that contributes to autophagosome formation) partially prevents FoxO3-mediated muscle loss (Mammucari et al., 2007). Other genetic models have confirmed the role of autophagy during muscle atrophy. For example, oxidative stress induced by the muscle-specific expression of a mutant superoxide dismutase protein (SOD1 G93A ) causes muscle atrophy mainly by activating autophagy, and attenuation of autophagy by shRNA-mediated knockdown of LC3 preserves muscle mass in SOD1 G93A transgenic mice (Dobrowolny et al., 2008). In addition, knockdown of the dihydropyridine receptor (DHPR), an L-type Ca 2+ channel, in adult muscle leads to increased levels of cytosolic neuronal nitric oxide synthase (nNOS) and FoxO3 activation, which induce oxidative stress and autophagosome formation, respectively (Piétri-Rouxel et al., 2010).
Autophagy is primarily considered to be a non-selective degradation pathway, but the significance of more selective forms of autophagy is becoming increasingly evident. Indeed, autophagy can trigger the selective removal of specific organelles, such as mitochondria via mitophagy. In mammals, parkin, PINK1, Bnip3 and Bnip3L have been shown to regulate mitophagy, and inactivation of the genes encoding these proteins leads to abnormal mitochondria ( Fig. 2 ) (Bothe et al., 2000 Hara et al., 2006). PINK1 recruits parkin to mitochondria, where parkin promotes mitophagy through ubiquitylation of outer mitochondrial membrane proteins that are recognized by p62, which brings autophagic vesicles to ubiquitylated mitochondrial proteins (Narendra and Youle, 2011 Youle and Narendra, 2011). Bnip3 and Bnip3L reportedly bind directly to LC3, and can therefore recruit the growing autophagosome to mitochondria (Hanna et al., 2012 Novak et al., 2010). In atrophying muscle, the mitochondrial network is dramatically remodeled following fasting or denervation, and autophagy via Bnip3 contributes to mitochondrial remodeling (Romanello et al., 2010 Romanello and Sandri, 2010). Expression of the fission machinery is sufficient to cause muscle wasting in mice, whereas inhibition of mitochondrial fission prevents muscle loss during denervation, indicating that disruption of the mitochondrial network is a crucial amplificatory loop of the muscle atrophy program (Romanello et al., 2010 Romanello and Sandri, 2010). Conversely, impairment of basal mitophagy is deleterious to muscle homeostasis, and leads to the accumulation of damaged and dysfunctional mitochondria (Grumati et al., 2010). Besides mitophagy, other forms of selective autophagy probably play important roles in the maintenance of skeletal muscle homeostasis. For example, a proper rate of nucleophagy seems essential for nuclear remodeling of muscle fibers, as indicated by nuclear envelopathies, a group of genetic disorders characterized by increased nuclear fragility and giant autophagosomes that contain nuclear components (Park et al., 2009).
Although available data are still limited to a few components of the autophagic machinery, the phenotypes of mice with muscle-specific inactivation of genes encoding autophagy-related proteins clearly demonstrate the essential role of autophagy in muscle homeostasis (see Fig. 2 and Table 1 ). Ablation of Atg7, the unique E1 enzyme of the autophagic machinery, causes disorganized sarcomeres and activation of the unfolded protein response, which in turn triggers myofiber degeneration this phenotype is associated with complete inhibition of autophagosome formation, leading to abnormal mitochondria, oxidative stress and accumulation of polyubiquitylated proteins (Masiero et al., 2009). These Atg7-null mice are affected by muscle weakness and atrophy, and they display several signs of myopathy. Another study showed that suppression of autophagy exacerbates fasting- and denervation-induced atrophy in Atg7-null mice (Masiero and Sandri, 2010). A similar phenotype was observed in mice with muscle-specific ablation of Atg5, another crucial component of the autophagy machinery (Raben et al., 2008). Another recent mouse study revealed that nutrient-deprivation autophagy factor-1 (Naf-1), a Bcl-2-associated autophagy regulator, is required for the homeostatic maintenance of skeletal muscle. Naf1-null mice display muscle weakness and markedly decreased strength, accompanied by increased autophagy, dysregulation of calcium homeostasis and enlarged mitochondria (Chang et al., 2012).
Recent genetic studies by the group of Eric N. Olson revealed a key role for histone deacetylases (HDACs) in the control of skeletal muscle homeostasis and autophagic flux (Moresi et al., 2012 Moresi et al., 2010) ( Table 1 ). Muscle-specific ablation of both HDAC1 and HDAC2 results in partial perinatal lethality, and HDAC1/2 double-knockout mice surviving postnatally develop a progressive myopathy characterized by impaired autophagy. HDAC1 and HDAC2 were found to regulate muscle autophagy by inducing the expression of autophagy genes. Notably, feeding HDAC1/2 knockout mice a high-fat diet releases the block in autophagy and prevents myopathy (Moresi et al., 2012). Another study by the same group also revealed roles for HDAC4 and HDAC5, as well as for the transcriptional muscle regulator myogenin, in modulating atrophy following denervation (Moresi et al., 2010). These studies demonstrated that myogenin activates the expression of the E3 ubiquitin ligases atrogin-1 and MuRF1, and that myogenin knockout mice fail to upregulate atrogin-1 and MuRF1 following denervation and are protected from atrophy. Similarly, mice lacking both HDAC4 and HDAC5 in skeletal muscle fail to upregulate myogenin and preserve muscle mass following denervation (Moresi et al., 2010).
The crucial role of the autophagy-lysosome system in skeletal muscles is confirmed by the fact that alterations to this process contribute to the pathogenesis of several genetic muscle diseases. Autophagy has a dual role in muscle homeostasis: it can be detrimental and contribute to muscle degeneration, but can also be a compensatory mechanism for cell survival. Congenital muscular dystrophies that are linked to the extracellular matrix (ECM) proteins collagen VI and laminin-2 illustrate the opposite effects that autophagy can have in skeletal muscles (Carmignac et al., 2011 Grumati et al., 2010). Our recent work indicated that autophagy plays a protective role against muscle weakness and wasting in Bethlem myopathy and Ullrich congenital muscular dystrophy, which are two inherited muscle disorders associated with collagen VI deficiency (Bernardi and Bonaldo, 2008 Grumati et al., 2010). A failure of the autophagic machinery is responsible for the inefficient removal and persistence of altered mitochondria in myofibers of Col6a1-null mice, and of Bethlem and Ullrich patients. Notably, reactivation of the autophagic flux in collagen-VI-deficient muscles (through diet or with pharmacological tools) can eliminate altered organelles and rescue the myopathic phenotype, showing promising therapeutic potential for counteracting muscle atrophy and weakness in these diseases (Grumati et al., 2010). Lack of collagen VI has a remarkable impact on molecules that are involved in the regulation of autophagy, decreasing beclin-1 and Bnip3 protein levels and causing persistent activation of the Akt [also known as protein kinase B (PKB)]-mTOR (mammalian target-of rapamycin) pathway, even during starvation (Grumati et al., 2010 Grumati et al., 2011a). However, the full details of the molecular axis that transduces collagen VI signals from the ECM to the autophagy machinery remain to be elucidated.
Further studies revealed that abnormal regulation of autophagy is involved in the pathogenesis of other mouse models of muscular dystrophies. Unlike mice with collagen VI deficiency, dy 3K /dy 3K mice [which lack laminin-2 and represent a model for merosin-deficient congenital muscular dystrophy type 1A (MDC1A)] display a general upregulation of autophagy-related genes, and pharmacological inhibition of autophagy significantly improves their dystrophic phenotype (Carmignac et al., 2011). Therefore, inappropriate regulation of autophagy is pathogenic in the two most common forms of congenital muscular dystrophy, which are both linked to deficiency of ECM proteins (collagen IV or laminin-2). How the absence of either of these two ECM proteins results in such opposing effects on autophagy remains undefined, but it is clear that alterations to the main components of muscle endomysial ECM have a marked impact on the regulation of autophagy.
Accumulation of autophagosomes occurs in many myopathies and represents the major feature of a group of muscle disorders named autophagic vacuolar myopathies (Malicdan et al., 2008). These myopathies are characterized by mutation of genes encoding proteins involved in lysosomal function, and include Pompe disease (caused by a defect in lysosomal acid α-glucosidase), Danon disease (caused by mutations of the LAMP2 gene) and X-linked myopathy with excessive autophagy (XMEA which is associated with mutations of the VMA21 gene) (Malicdan et al., 2008 Ramachandran et al., 2009). It remains to be established whether accumulation of autophagosomes in these myopathies contributes to muscle damage or, conversely, whether it is a compensatory effect. Indeed, for many years the pathogenic defects of Pompe disease were attributed to impairment and rupture of lysosomes. However, this view was challenged by the newly proposed idea that the massive accumulation of autophagosomes (resulting from defective autophagy) is the main event causing myofibrillar disorganization and altered endocytic trafficking (Fukuda et al., 2006a Fukuda et al., 2006b). Recently, additional inherited muscle disorders were shown to be related to increased autophagy. For example, mutations that inactivate MTMR14 (also known as Jumpy), a phosphatase counteracting the action of Vps34 in autophagosome formation and reducing the autophagy flux, have been associated with centronuclear myopathy (Vergne et al., 2009).
Together, the above findings in normal and diseased muscle clearly indicate that a proper balance of the autophagic flux is essential for maintaining healthy skeletal muscle, and that unbalanced autophagy is a main pathogenic mechanism in many muscle diseases. Thus, too much autophagy impairs myofiber homeostasis, causing excessive removal of cellular components that are needed for normal activities and leading to muscle atrophy when excessive catabolic activity is sustained for long periods. Insufficient autophagy also impairs myofiber homeostasis, leading to accumulation of damaged or dysfunctional cell components, with structural and functional impairment causing muscle weakness.
Besides its obvious pathogenic role in several muscle diseases, it is also conceivable that a slight and chronic unbalance of the autophagic process might significantly contribute to sarcopenia, the excessive loss of muscle mass that occurs in the elderly. An abnormal regulation of autophagy in aged individuals might interfere with the contractile properties of myofibers and render them less stable and more susceptible to contraction-induced damage, eventually leading to muscle atrophy (Cuervo, 2008). Although few studies have investigated autophagy in skeletal muscle of aged individuals, recent data confirmed that unbalanced autophagy might contribute to sarcopenia. Findings in rat muscles showed an age-related decline in autophagic degradation and a concomitant age-related increase in oxidative damage and apoptosis, which were both negatively correlated with autophagy. Interestingly, a constant autophagic stimulus, such as caloric restriction, was found to ameliorate the physiological state of muscles during aging (Wohlgemuth et al., 2009). During aging, there is also a progressive deterioration of mitochondrial function and activation of autophagy. Forced expression of proliferator-activated receptor gamma coactivator-1α (PGC1α a master gene of mitochondrial biogenesis) ameliorates loss of muscle mass and prevents the age-related increase in autophagy (Wenz et al., 2009). An interesting link between autophagy and aging was recently described in Drosophila, where the maintenance of a normal autophagic flux in aged muscles was found to induce a beneficial extension of lifespan. Selective activation of autophagy in skeletal muscle via FoxO prevents accumulation of protein aggregates and, consequently, muscle weakness, thus providing the first genetic evidence correlating FoxO, autophagy and healthy muscles to lifespan extension (Demontis and Perrimon, 2010).
Other recent work has demonstrated a link between physical exercise and autophagy in muscle. We have shown that physical exercise is very effective in stimulating autophagy in skeletal muscles, and that the accompanying clearance of damaged cell components and dysfunctional mitochondria is crucial for muscle homeostasis (Grumati et al., 2011b). Further work extended these observations and demonstrated that exercise-induced autophagy plays an important and previously unrecognized role in muscle metabolism (He et al., 2012). These findings provide a mechanism for explaining the well-known beneficial effects of physical activity in healthy individuals.
Responses of Musculoskeletal Tissues to Disuse and Remobilization
Muscle atrophy may occur following fractures, particularly those with severe comminution. A stable repair with anatomic reduction is vital to encourage early weight bearing, joint motion, and use of the limb. Distal femoral fractures treated with limb immobilization in extension for 3 to 7 weeks resulted in limb hyperextension, generalized muscle atrophy, abducted gait, and limited range of joint motion. 205 Lesions in muscle biopsies included fiber size variability, increased fibrosis, and focal necrosis. Histochemical and morphometric studies showed significant type I fiber atrophy in the vastus lateralis muscle, with a reduction of the number of type I fibers. Atrophic changes in the gastrocnemius and biceps femoris muscles were not significant. The atrophy seen in the vastus lateralis muscle may be a result of immobilizing the limb in extension, which results in shortening of this muscle group. Immobilization of a muscle in a shortened position results in preferential atrophy caused by a reduced number of sarcomeres in series and reduced protein synthesis. In contrast, passive stretch of muscles in a lengthened state promotes muscle growth and may explain the relative sparing to the biceps femoris and gastrocnemius muscles.
A follow-up experimental study evaluated the effect of splinting in extension for 2 weeks following trauma to the distal portion of the quadriceps femoris muscle in dogs. 206 Flexion of the stifle joint was limited after splinting. A reversible type I fiber atrophy of the vastus lateralis, biceps femoris, and gastrocnemius muscles occurred. Early type II fiber atrophy was seen in a few muscles. Multifocal fiber necrosis was the only irreversible change seen. Relative fiber percentages did not change appreciably during splinting or recovery. 206
MATERIALS AND METHODS
The use of mouse models in this study was approved by Animal Experimentation Ethics Committee of the University of Barcelona under protocol number DAAM 8563. The source of mouse models used in the study, the hindlimb immobilization protocol and the in vivo analysis of atrogene promoter activity are detailed in Supplementary Data .
Cell lines and cell culture
C2C12 and 293T cell lines were obtained from the American Type Culture Collection (ATCC)-LGC Standards (Middlesex, England, UK). The culture conditions for myotube differentiation and starvation are detailed in Supplementary Data .
Antibodies, and DNA and RNA oligonucleotides
The antibodies used in western blot, and in the immunostaining of mouse muscle samples and C2C12 myotubes are detailed in Supplementary Data . DNA oligonucleotides used as primers in quantitative real-time polymerase chain reaction (qRT-PCR) are listed in the Supplementary Data . Lastly, RNA oligonucleotides used in RNA interference are described in the Supplementary Data .
Gene and protein expression
RNA extraction and subsequent analysis of gene expression by qRT-PCR, and transcriptional studies by luciferase reporter assays are described in Supplementary Data . Analysis of protein expression in mouse tissue samples and C2C12 myotubes as well as myofibers’ CSA analysis of muscle sections are described in Supplementary Data .
Statistical analysis of data shown was performed using GraphPad Prism for Mac version 5.0a (GraphPad Software Inc., La Jolla, CA, USA). Normal distribution of the data was determined with Kolmogorov–Smirnov test. Statistical significance of the normally distributed data was assessed with a t-test and with a non-parametric Mann–Whitney U test for those with non-normal distribution. Error bars in histograms represent standard errors of means. Relevant comparisons were labeled as either significant at the P ≤ 0.001 (***), P ≤ 0.01 (**) or P ≤ 0.05 (*) levels, or non-significant (ns) for values of P > 0.05.
Loss of skeletal muscle mass occurs frequently in clinical settings in response to joint immobilization and bed rest, and is induced by a combination of unloading and inactivity. Disuse-induced atrophy will likely affect every person in his or her lifetime, and can be debilitating especially in the elderly. Currently there are no good therapies to treat disuse-induced muscle atrophy, in part, due to a lack of understanding of the cellular and molecular mechanisms responsible for the induction and maintenance of muscle atrophy. Our current understanding of disuse atrophy comes from the investigation of a variety of models (joint immobilization, hindlimb unloading, bed rest, spinal cord injury) in both animals and humans. Under conditions of unloading, it is widely accepted that there is a decrease in protein synthesis, however, the role of protein degradation, especially in humans, is debated. This review will examine the current understanding of the molecular and cellular mechanisms regulating muscle loss under disuse conditions, discussing the similarities and areas of dispute between the animal and human literature.
This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.
Medical conditions that cause muscle wasting
Muscle wasting is a loss of muscle mass due to the muscles weakening and shrinking. There are several possible causes of muscle wasting, including certain medical conditions, such as amyotrophic lateral sclerosis.
The symptoms of muscle wasting depend on the severity of muscle mass loss, but typical signs and symptoms include:
- reduced muscle strength
- an impaired ability to perform physical activities
- a decrease in muscle size
Diagnosis usually occurs after a medical history review and physical examination. The cause of muscle wasting is sometimes evident. In other instances, a doctor may need to perform additional tests to confirm a diagnosis.
Medical conditions that can cause muscle wasting include the following:
Share on Pinterest A number of medical conditions can cause muscles to weaken.
Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects nerve cells throughout the body.
Usually, the nerve cells in the brain and spinal cord send messages to the muscles to move.
In people with ALS, the nerve cells that control voluntary movement die and stop sending the signals that allow movement. Eventually, due to lack of use, the muscles atrophy.
Doctors do not know what causes ALS.
Muscular dystrophy is a genetic condition that leads to progressive muscle weakness and muscle wasting.
There are several types of muscular dystrophy, which vary in their age of onset and specific symptoms.
Multiple sclerosis (MS) is a type of autoimmune disease that affects the myelin that surrounds the nerve fibers.
The condition causes damage to the nerves, which affects the muscles in turn. The damaged nerves lose their ability to trigger muscle movement, leading to atrophy.
The severity of the damage affects the rate of muscle loss.
Spinal muscular atrophy is a condition that is similar to muscular dystrophy.
The disease is genetic and occurs due to a loss of motor neurons, which are cells that control the muscles. The muscles in the body gradually weaken.
Although it weakens most of the muscles in the body, spinal muscular atrophy usually affects the muscles closer to the center of the body most severely.
Some other causes of muscle wasting, which are not medical conditions in themselves, include:
Inactivity for extended periods
Prolonged inactivity, such as bed rest, can lead to a loss of muscle mass. Bed rest may be necessary due to injuries or illnesses that leave a person unable to move.
According to research , muscle wasting can develop within 10 days in healthy older adults on bed rest. Due to the muscle wasting, a 40% decrease in muscle strength can occur within the first week.
People with malnutrition have a significantly inadequate nutritional intake, and this can cause muscle loss, leading to muscle wasting.
Malnutrition has a variety of possible causes, including anorexia nervosa, cancer, and persistent nausea.
Muscle loss occurs gradually due to aging.
The authors of a 2013 study noted that significant changes to leg muscle mass occur after the age of 50 years when a muscle loss of 1–2% a year is typical.
They also highlighted research showing that between 20 and 80 years of age, the average person loses 35–40% of the muscle mass in their legs.
Getting treatment for muscle wasting is vital for a person’s overall well-being.
Muscle wasting occurs with many types of illness and disease. According to research from 2017, muscle wasting contributes to a worse prognosis in diseases such as heart failure, sepsis, and cancer.
Treatment may, in part, depend on the underlying condition leading to muscle loss. In some cases, treating the illness may prevent further muscle wasting and help reverse the condition.
Additional treatment options may include:
Exercise to build strength is one of the main ways to prevent and treat muscle wasting. The type of activities that doctors recommend will depend on the cause of atrophy. For example, certain underlying conditions may limit specific exercises.
Focused ultrasound therapy
Focused ultrasound therapy is a relatively new treatment for muscle wasting. It involves directing beams of high-frequency sound waves at specific areas on the body. The sound waves stimulate muscle contraction, which may help decrease muscle loss.
Proper nutrition helps the body build and retain muscle. Adopting a diet that provides sufficient calories, protein, and other nutrients that promote muscle development may help treat muscle wasting.
Physical therapy may involve various techniques to prevent muscle wasting. Therapists may recommend certain exercises depending on the person’s condition.
Physical therapy is also helpful if a person is on bed rest. Therapists may perform passive exercises if an individual is unable to move. This type of exercise involves the therapist moving the legs and arms to exercise the muscles.
Muscle wasting involves muscle loss or atrophy and usually happens gradually. It can occur because of a variety of conditions, including ALS, muscular dystrophy, and MS.
As muscle wasting can affect a person’s strength and their ability to perform everyday activities, it can greatly reduce their quality of life.
Treating the condition as soon as possible may prevent or slow significant muscle loss. Anyone who thinks that they may have muscle wasting should see a doctor.
In some cases, it is possible to reverse muscle wasting, but it may take time. When muscle wasting is not reversible, treatment may at least slow the loss of muscle. Treatment may include a combination of exercises, nutritional changes, and physical therapy.
This work was funded by was funded by the National Institutes of Health, Award number: R15 AR069913/AR/NIAMS.
Integrative Muscle Metabolism Laboratory, Exercise Science Research Center, Department of Human Health Performance and Recreation, University of Arkansas, Fayetteville, AR, 72701, USA
Megan E. Rosa-Caldwell & Nicholas P. Greene
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MER and NPG wrote and edited the manuscript and give final permission for publication.