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Therapies for Improving Muscle Function in Neuromuscular Disorders

Lynch, Gordon S.

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Exercise and Sport Sciences Reviews: October 2001 - Volume 29 - Issue 4 - p 141-148
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Muscular dystrophy is a term that covers a diverse group of inherited disorders characterized by progressive skeletal muscle weakness and wasting. The most severe and well described of the muscular dystrophies is Duchenne muscular dystrophy (DMD), which is caused by a variety of mutations and deletions in the dystrophin gene on chromosome Xp21. Dystrophin is associated with a large complex of membrane glycoproteins, referred to as the dystrophin-glycoprotein complex (DGD) or dystrophin-associated protein (DAP) complex. The DAP complex links dystrophin in the subsarcolemmal cytoskeleton directly with actin and also with agrin and laminin-2 (merosin) in the extracellular matrix. The functional role of the dystrophin-DAP complex appears to be associated primarily with the stability of the sarcolemma during muscle contraction (12). Recent evidence also suggests that the DAP complex may also have a role in molecular signaling, specifically in the neuronal nitric oxide synthase (nNOS)-mediated regulation of blood flow to contracting muscles (5). In the absence of dystrophin expression, the skeletal muscles of boys with DMD are susceptible to contraction-induced damage and undergo continuous cycles of degeneration and regeneration of muscle fibers that lead to a progressive muscle wasting. DMD patients become dependent on a wheelchair usually before their early teens and have only 25% of the muscle mass of healthy children, the relentless muscle wasting leading to respiratory or heart failure by their early 20’s. There is a profound need for therapeutic intervention strategies that aim to ameliorate the dystrophic condition and improve the quality of life for these patients.

Therapeutic approaches for muscular dystrophy fall into two classes: those that attempt to ameliorate the dystrophic condition through pharmacologic interventions, or those that attempt to overcome the gene defect. Although gene- and cell-based therapies show the most promise in providing a cure for these neuromuscular disorders, these techniques are far from perfected. A rational understanding of dystrophic pathology may yet lead to effective pharmacologic interventions. A summary of the potential sites of potential intervention in the pathogenesis of muscular dystrophy is presented in Figure 1. Although not curing the genetic defect, pharmacologic-based treatments are also extremely important, both in their own right and also as adjunctive therapies for increasing the efficacy of genetic- or cell-based approaches.

Figure 1
Figure 1:
A summary of the potential sites of intervention in the pathogenesis of muscular dystrophy. Gene therapies aim to correct the defect in the dystrophin gene to enable expression of the dystrophin protein. Myoblast transfer therapy (and other related cell therapies) involve the transplantation of normal myoblasts into dystrophin-deficient muscle so as to create a pool of normal myoblasts capable of fusing with dystrophic (dystrophin-deficient) muscle fibers and restoring dystrophin expression. The lack of dystrophin and the disruption to the DAP complex (DGC) is thought to render the dystrophic muscle fibers more susceptible to injury during contraction because of a lack of membrane stability. When a muscle fiber is activated and then stretched forcibly (pliometric or “eccentric” contraction), mechanical damage may occur to the contractile filaments and to the cytoskeletal network of proteins that maintain structural stability. If damage is severe, then membrane integrity can be compromised allowing an influx of Ca2+ into the cytosol. If the cell can maintain normal intracellular [Ca2+], then fiber degeneration will be minimized. If intracellular [Ca2+] cannot be regulated, then a number of Ca2+-activated proteases and phospholipases will be activated, leading to muscle fiber degeneration and subsequent regeneration. In the case of DMD, the continuous cycle of injury, degeneration and regeneration, is thought to exhaust the inherent muscle fiber satellite cell population, compromising the muscle repair process. Instead of complete regeneration of the injured muscle fibers, the damaged tissue is often replaced with noncontractile connective tissue and fat. Pharmacologic therapies aim to either reduce the severity of the muscle damage by attempting to control [Ca2+] (e.g. Ca2+ channel blockers), enhance the repair of damaged, regenerating muscle fibers (e.g. β2-agonists, IGF-I), or in some cases, promote the expression of dystrophin (e.g. aminoglycosides).


Transplantation of normal myoblasts into dystrophin-deficient muscle potentially creates a pool of normal myoblasts capable of fusing with dystrophic muscle fibers and restoring dystrophin. In dystrophic mdx mice, myoblast transfer therapy (MTT) experiments have shown that normal myoblasts injected into dystrophin-deficient muscles can fuse with dystrophic myoblasts and express dystrophin at the sarcolemmal membrane. Clinical trials using MTT for treating DMD have so far proved less than successful. Despite the injection of many millions of myoblasts into affected muscles of DMD patients, problems with low spread and poor survival of myoblasts and immune rejection have resulted in very few of the fibers in the injected muscles expressing dystrophin and no differences in muscle strength (10).

Since the late 1990’s, stem cell therapy as a treatment for muscular dystrophy has became a realistic possibility (14). In this approach, bone marrow cells that differentiate into myogenic cells can be engineered with genes coding for dystrophin and dystrophin-associated proteins such as utrophin. The rationale is that the bone-marrow–derived myogenic precursors migrate into degenerated muscle, undergo differentiation, and help to regenerate damaged muscle fibers. In dystrophin-deficient mdx mice, a model for DMD, introducing a dystrophin or utrophin sequence into germal cells can correct the dystrophic phenotype. The molecular structure of utrophin is very similar to that of dystrophin, the missing protein in DMD. Utrophin is normally localized at the neuromuscular junction, but variable amounts are found at the sarcolemma of muscles of the mdx mouse and DMD patients. Utrophin minigenes have been generated, and in transgenic mdx mice, utrophin expression lowered serum creatine kinase levels and reduced the number of centrally nucleated (regenerated) myofibers. In animal experiments, a high expression of the utrophin gene in skeletal muscle can reverse the dystrophic pathology and improve the functional properties of skeletal muscles from mdx mice (7). Utrophin replacement for dystrophin remains a viable approach for treating muscular dystrophy.

Despite the fact that a cure for DMD and other muscular dystrophies will likely come from either gene therapy, stem cell therapy, or myoblast transfer (or combinations of these therapies), there are many unresolved problems that continue to hamper this research. These include: the limitation of the spread of expression from injection sites in the muscle, the longevity of expression, the need for systemic delivery, vector design and carrying capacity, and difficulties with immunosuppression (10). Sadly, until these techniques are perfected, boys with DMD will die and patients with other less severe neuromuscular conditions will continue to lose muscle mass and function.

Mechanisms of Muscle Wasting in Neuromuscular Disorders

The mechanisms underlying muscle wasting, and the molecular signaling pathways controlling muscle growth, hypertrophy, and plasticity, have been reviewed extensively (13), and the purpose of this review is not to repeat this information, but instead use it as a basis from which the efficacy of potential therapeutic pharmacologic or nutrition strategies can be evaluated. These alternative therapies are directed toward preserving existing muscle tissue, enhancing muscle regeneration, and promoting muscle growth. Many of these treatments can also be adjunctive therapies for increasing the efficacy of genetic- or cell-based therapies.

There are at least three different pathways for protein breakdown in skeletal muscle, proteolysis by: (1) lysozomal proteases such as cathepsins; (2) nonlysozomal intracellular Ca2+-dependent proteases such as calpains; and (3) nonlysosomal ATP-ubiquitin–dependent proteolytic proteases, such as proteasomes (8). The lack of dystrophin in the muscles of DMD patients is thought to contribute to a significant accumulation and elevation of intracellular Ca2+, triggering an increase in calpain activity. Traditionally, proteolysis by calpain was thought to be responsible for the degradation of muscle in DMD, however, recent studies have shown that the ATP-ubiquitin–dependent pathway is responsible for the majority of the muscle protein breakdown. Experimentally, muscles from patients with DMD and other neuromuscular disorders (including patients with amyotrophic lateral sclerosis [ALS], peripheral neuropathies, and polymyositis) showed abnormal increases in proteasomes and ubiquitin, compared with muscles from healthy subjects (8). It has been proposed that in muscular dystrophy, calpains are involved in the early stages of muscle fiber breakdown and that proteasomes participate in the latter stages of muscle degradation (8).

Rationale for Different Treatments

The aim of any treatment for muscle wasting is to restore, maintain, or improve muscle size and strength. Slowing the loss of muscle tissue will preserve muscle function. Restoring or increasing muscle tissue to former or higher levels will optimize the potential for improving muscle function. Many therapeutic trials have been undertaken with the purpose of ameliorating (or potentially curing) the muscular dystrophies. The therapeutic approaches include the use of compounds that increase muscle size, such as anabolic steroids, β2-adrenoceptor agonists (β2-agonists), growth hormone secretion modulators, and growth factors and related cytokines; compounds that preserve muscle size and reduce inflammation, such as corticosteroids; compounds designed to modulate intracellular [Ca2+], such as Ca2+ channel blockers, and chelating agents; as well as other treatments such as xanthine oxidase inhibitors and immunosuppressives; and nutritional strategies such as amino acid and vitamin supplementation (10). Some of the therapies proposed for treating muscular dystrophy (and related muscle wasting disorders), the rationale for each approach, and their potential and drawbacks, are summarized in Table 1.

Table 1
Table 1:
Summary of some of the therapies proposed for treating muscular dystrophy (and other muscle wasting disorders)

Calcium channel blockers, growth hormone inhibitors, and vitamin E have all proved unsuccessful, ie they provided no beneficial effects. Several trials with corticosteroids, such as prednisone and deflazacort, have been shown to provide some level of improvement in the dystrophic condition, evidenced by small but significant improvements in muscle strength. However, not all trials have been conclusive and the long-term use of glucocorticoids has often been accompanied by side effects, including weight gain. Although a beneficial effect of prednisone on DMD patients has been demonstrated, the mechanism of its action is not clear although it is linked to the antiinflammatory properties of these compounds. Corticosteroids have a general catabolic effect on muscle and the rationale for their use in DMD has been to counter the effects of inflammation and preserve existing muscle fibers, hence the observed improvement in strength (14). Prednisone has also been reported to have nonspecific membrane-stabilizing effects, and it is possible that it may also prove efficacious for other dystrophies including the sarcoglycanopathies and facioscapulohumeral muscular dystrophy (FSHD) (14).

Rather than increasing muscle size and strength, the use of glucocorticoids maintains or actually reduces muscle fiber size (see Figure 2). Reducing fiber size could be one way to reduce the ongoing damage to the dystrophic muscle since smaller caliber fibers appear to be less susceptible to contraction-induced injury (12). Numerous studies have demonstrated that skeletal muscles of mdx dystrophic mice have a greater susceptibility to injury, particularly when maximally activated muscles are stretched during pliometric (eccentric) contractions (12). Dystrophin is thought to provide a link between the cytoskeleton and the laminin in the extracellular matrix, leading to the hypothesis that dystrophin maintains the integrity of the sarcolemma, both in quiescent fibers and during muscle contractions. This hypothesis has been supported by reports of differences between muscle fibers of mdx compared with control mice in relation to the release of enzymes from fibers, the stiffness of sarcolemma, the response to osmotic shock, and the magnitude of the damage following pliometric contraction protocols (12).

Figure 2
Figure 2:
Two approaches that attempt to modify dystrophic muscle pathology. In the case of the untreated dystrophic muscle (A), analysis of cross-sections reveals many centrally nucleated fibers of variable size, and extensive inflammation with infiltration of mononuclear cells. Central nucleation indicates that the fiber is newly regenerated. Administration of a corticosteroid (B) will generally be catabolic to the muscle, reducing fiber size. A reduction in the inflammatory response has also been reported with the use of these compounds. It is possible that the smaller caliber fibers are less susceptible to contraction-induced muscle damage, reducing the cycles of degeneration and repair. Administration of an anabolic agent (C) will generally increase muscle fiber size and strength, enhance muscle repair, and in some cases reduce inflammation. Whether promoting the formation of larger fibers increases the susceptibility of the dystrophic muscle to contraction-induced damage is a topic of on-going research.

Although treatment with corticosteroids might be expected to reduce muscle fiber size, powerful anabolic agents such as the β2-adrenoceptor agonist, clenbuterol, or growth factors such as insulin-like growth factor-I (IGF-I) would be expected to increase muscle fiber size and therefore increase overall muscle strength (Figure 1). It has been postulated that any intervention that promotes muscle growth and fiber maturation without supplying the missing protein, nutrient, or metabolites will eventually aggravate the dystrophic pathology (7). In conditions where muscle wasting is severe, such as in DMD patients or in the very frail elderly, the use of an anabolic agent may be have greater therapeutic potential if such a strategy can increase muscle size and strength and therefore restore some level of muscle function. The drawback of this approach may be that the an increase in fiber size may increase the likelihood of contraction-induced injury and hence hasten the muscle degenerative process. Clearly, this hypothesis merits further testing.

Interfering with the Ubiquitin Pathway Using Proteasome Inhibitors

The therapeutic potential of pharmacological proteasome inhibitors for treating muscle wasting diseases including muscular dystrophy has been considered (2). The 90-kDa heat-shock protein (HSP90) and ubiquitin are upregulated in regenerating muscle fibers of DMD patients (2). A significant upregulation of HSP90 and ubiquitin in regenerating fibers and developing infantile fibers suggest that during myogenesis, HSP90 and ubiquitin are largely regulated by the activation of developmental mechanisms rather than being primarily disease-related. Modulation of this stress response could promote myogenesis and provide a new therapeutic approach for myopathies (2).


Testosterone administration has been proposed as a possible therapy to counteract the muscle atrophy and weakness that occurs with prolonged weightlessness or bedrest, however, its ability to ameliorate the loss of muscle mass and preserve strength (in the latter condition) has not been demonstrated. In patients with myotonic dystrophy, a condition where muscle wasting may be associated with low circulating levels of adrenal androgens, testosterone supplementation increased muscle mass but did not improve muscle strength (14). Similarly, approaches using anabolic steroids as a means of improving the dystrophic pathology in DMD have generally proved unsuccessful (7). However, based on a pilot study that showed a positive effect of the anabolic steroid oxandrolone (Oxandrin) on the muscle strength of 10 boys with DMD, a clinical trial was recently initiated by the Muscular Dystrophy Association (MDA), and results are expected in 2001.

Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are abundant circulating steroids in humans. In patients with myotonic dystrophy, serum concentrations of DHEA-S are lower than in healthy subjects. Patients with myotonic dystrophy administered DHEA-S showed improved activities of daily living, increased muscle strength, and decreased myotonia (14). Although the data for this pilot study were encouraging, further research employing larger patient numbers are necessary before such a therapy would be considered for this and other neuromuscular disorders. Among the supplements promoted as having antiaging benefits are those that claim to enhance growth hormone or testosterone levels, including androstenediol and androstenedione. In a number of studies, these testosterone precursors have been found ineffective for increasing serum testosterone concentrations or for enhancing the adaptations to resistance training in normotestosterogenic men.


Growth hormone administration has been advocated as a countermeasure against the atrophy and weakness common to many neuromuscular disorders, including sarcopenia (the age-related loss of muscle mass). As a treatment for muscular dystrophy, growth hormone therapy was associated with an accelerated loss of function in some DMD patients (7). Conversely, growth hormone deficiency or treatment with growth hormone inhibitors produced a milder dystrophic phenotype in other DMD patients (7). Similarly, thyroxin administration increased the pathology in the muscles of mdx mice whereas thyroid deficiency reduced it (7).

IGF-I mediates many of the anabolic properties of GH and is involved in regulating protein turnover. IGF-I is a potent anabolic agent in skeletal muscle responsible for increasing rates of protein and nucleic acid synthesis, as well as inhibiting protein degradation. Studies examining the potential for IGF-I treatment in conditions where muscle wasting is indicated have not been conclusive. IGF-I has been proposed for clinical trials for patients suffering from muscle wasting because of its potential for increasing the rate of muscle regeneration following injury and its ability to offset the muscle atrophy concomitant with glucocorticoid treatment and contraction-induced injury (11). Experiments on different models of transgenic mice have also yielded inconsistent findings. High local expression of IGF-I in the muscles of transgenic mice did not prevent hindlimb-unloading atrophy, whereas virally-delivered IGF-I genes induced local skeletal muscle hypertrophy and attenuated age-related skeletal muscle atrophy, restoring and improving muscle mass and strength in aged mice (11).

In terms of its potential for treating muscular dystrophy, IGF-I has been shown to significantly reduce the rate of proteolysis in the skeletal muscles of the 129P1/ReJ-Lama2dy (129 ReJ dy/dy, laminin-deficient) dystrophic mouse (11). In the hind limb muscles of the mdx mouse, muscle wasting is not observed until the end of the life-span, and even then the wasting is minor compared with what is observed in the muscles of the 129 ReJ dy/dy mouse. In another recent study, treatment of 129 ReJ dy/dy mice with IGF-I for 4 weeks increased the mass of the fast-twitch extensor digitorum longus (EDL) and soleus muscles by 20% and 29%, respectively, and increased maximum force (Po) by 40% and 32%, respectively (11).

Although the effects of IGF-I on animal models of muscle wasting have been impressive, studies in humans have so far produced less dramatic results. For example, studies intended to ameliorate age-related muscle wasting (sarcopenia) by administering growth hormone (GH) and attempting to increase circulating IGF-I levels have proved less effective. The supplementation of IGF-I in healthy people with normal GH levels has, in some subjects, been associated with some disruption of the insulin/glucagon system. Of particular concern is evidence suggesting that IGF-I signaling and elevated IGF-I levels may be implicated in the development of prostate, colorectal, and lung cancers. Although on first impression it would appear that these negative effects of IGF-I administration outweigh any potential beneficial effects, it should be remembered that in very serious muscle disorders such as DMD, such an intervention could potentially restore some level of lost function and improve the quality of life for patients in the end stages of their condition. For treating generalized muscle wasting such as that in the very frail and elderly, research into the development of lower dose treatments are required to develop strategies that limit any potential undesirable side effects yet restore muscle size and function and promote independent living. Clearly, the therapeutic use of such growth factors is deserving of more focused research, especially for muscular dystrophy and aging. Researchers must be mindful that promoting muscle fiber growth is not always desirable, particular if treatment is associated with concomitant slow to fast fiber transformations that might deleteriously predispose the affected muscles to an increased likelihood for contraction-induced injury and a possible aggravation of the dystrophic pathology.


A number of the cytokines (including the interleukins-10, −13, and −15) have been proposed as having anabolic effects on skeletal muscle or capable of modifying contractile function. Although primarily implicated for treating neurological conditions, leukemia inhibitory factor (LIF) has also been proposed for treating other disorders where muscle wasting is indicated. LIF treatment been shown to ameliorate dystrophic symptoms in the diaphragm muscles of mdx mice, as evidenced by improved histology (maintenance of fiber integrity and reduced necrosis) and functional properties following treatment (10). Further studies are required to determine the efficacy of LIF for ameliorating sarcopenia and other muscle wasting conditions.

The potential of these cytokines for ameliorating muscle wasting associated with neuromuscular disorders has generally received limited attention. Interleukin-15 (IL-15) is a recently discovered growth factor that is highly expressed in skeletal muscle, stimulates muscle fibers to accumulate increased amounts of contractile proteins, stimulates myogenic differentiation, and is thought to play a role in skeletal muscle fiber growth in vivo (3). Most importantly, IL-15 has recently been shown to ameliorate muscle wasting in a rat model of cancer cachexia by antagonizing muscle protein breakdown through inhibition of the ATP-ubiquitin-dependent proteolytic pathway (3). The potential for IL-15 as a treatment for muscle wasting associated with muscular dystrophy or sarcopenia is deserving of attention.

β2-adrenoceptor Agonists

Although traditionally used for the treatment of bronchial ailments, especially asthma, it quickly became apparent that high doses of some β2-agonists, including the most well known, clenbuterol, had the ability to increase skeletal muscle mass and decrease body fat in livestock and rodents (9). Not surprisingly, there have been numerous studies that have focused primarily on therapeutic applications of the anabolic properties of β2-agonists, such as clenbuterol, for reversing the muscle atrophy observed with aging, denervation, muscle unloading, and muscle wasting diseases such as muscular dystrophy, and ALS (9,12). Although clenbuterol and other β2-agonists increase muscle mass in a variety of species, there are major inconsistencies regarding their effects on the functional properties of skeletal muscles of normal and diseased skeletal muscle. These studies on rats and mice have employed high (mg/kg) doses of clenbuterol administered to the animals daily over a period of several weeks or months. The majority of studies report only minor (or no) improvement in the force producing capacity and maximal power output of isolated muscles following chronic, high-dose clenbuterol administration and even fewer changes following lower, more physiological (μg/kg) doses (9). In many cases, the force output per muscle cross-sectional area is actually reduced following clenbuterol administration, indicating the intrinsic force producing capacity of the muscles following treatment does not keep pace with the obvious increases in muscle mass (9). The lack of effect of clenbuterol to modify the force and power output of the diaphragm muscles of the mdx mouse (10) indicates that β2-agonist therapy has yet to be optimized for potential clinical application for DMD. β2-agonists including clenbuterol and salbutamol have also been used to increase the muscle tissue mass for cardiac assist surgery where, in conjunction with electrical stimulation, a portion of the latissimus dorsi muscle is wrapped around the heart and stimulated to aid contraction of the ventricle. Although high doses of β2-agonists have demonstrated muscle anabolic properties, they are often associated with numerous undesirable side effects including increased heart rate and muscle tremor, factors that have so far limited their therapeutic potential (9).

A pilot clinical trial investigating the efficacy of the β2-agonist albuterol for treating FSHD revealed general improvements in lean body mass and strength, results that were particularly encouraging and that formed the basis for a larger, year-long trial (9). The MDA is currently supporting a double blind study designed to test whether albuterol treatment will yield a significant improvement in the muscle mass of boys with DMD. The powerful muscle anabolic effects of some β2-agonists means that they have potential for improving muscle strength and improving the quality of life for patients with DMD, most especially when other interventions have proved ineffective. β2-agonist therapy might prove efficacious for treating muscle wasting disorders but most likely only when they are used in combination with other treatments and only when their side effects can be reduced significantly.


Creatine Monohydrate

Interest in creatine monohydrate (Cr) as a nutritional supplement and ergogenic aid for athletes has surged in recent years (15). After cellular uptake, Cr is phosphorylated to phosphocreatine (PCr) by the creatine kinase (CK) reaction with the use of ATP. At subcellular sites with high energy requirements, eg at the myofibrillar apparatus during muscle contraction, CK catalyzes the phosphorylation of PCr to ADP to regenerate ATP. PCr is therefore available as an energy source, serving as an energy buffer and an energy transport vehicle. Ingestion of creatine increases intramuscular Cr, as well as PCr concentrations, and can lead to enhanced exercise (sprint) performance. Additional benefits of Cr supplementation have also been observed for high-intensity, long-endurance tasks, eg shortening of recovery periods after physical exercise (15).

Therapeutic application of creatine supplementation for neuromuscular disorders has received some attention. In DMD, the decreased intramuscular concentration of creatine has been postulated to contribute to the deterioration of intracellular energy homeostasis and the aggravation of muscle degeneration and weakness (15). In skeletal muscle cells from mdx dystrophic mice, pretreatment with creatine increased cellular PCr levels and improved the regulation of cytosolic [Ca2+] in myotubes, whereas in patients with mitochondrial cytopathies, creatine monohydrate supplementation improved hand grip strength but had no effect on lower intensity aerobic activities (15). A better indication of the therapeutic potential of creatine for treating neuromuscular disorders will come from the findings of current (2001) MDA-supported multicenter trials testing the effectiveness of creatine monohydrate ingestion in patients with ALS and DMD.


Glutamine is the most abundant free amino acid in the body and muscle protein synthesis is correlated directly with intramuscular glutamine concentration in animals. Given that glutamine administration appears to be the most direct way of increasing the free amino acid pool within skeletal muscle, glutamine supplementation may be used to limit the protein loss in DMD or other muscle wasting conditions (6). Boys with DMD given an acute oral and intravenous administration of L-glutamine over a period of two days showed a reduced breakdown of overall protein (6). Therefore, it is possible that long-term glutamine administration may be an effective treatment for DMD by slowing protein degradation and maintaining muscle protein levels. Whether glutamine treatment can improve muscle function in patients with muscle wasting is deserving of further attention. A multicenter randomized placebo-controlled double-blind study supported by the MDA is currently (2001) under way to assess efficacy and safety of glutamine and creatine monohydrate treatment in boys with DMD. The patients enrolled in this trial will receive creatine monohydrate or glutamine or an inactive placebo orally for six months, and muscle strength will be assessed over the course of treatment.

β-hydroxy-β-methylbutyric Acid (HMB)

Another nutritional strategy that has been proposed for treating muscle wasting, with relevance to neuromuscular disorders, is supplementation with the leucine metabolite, HMB. Although there have been numerous reports of HMB supplementation reducing exercise-related muscle damage and muscle protein breakdown in athletes, the application of HMB for muscle wasting conditions has only recently gained attention. HMB in combination with l-glutamine and l-arginine was found effective in slowing the course of muscle wasting in patients with established acquired immunodeficiency syndrome (4). Further work is needed to determine the efficacy of this nutritional strategy for ameliorating muscle wasting and improving muscle function in patients with neuromuscular disorders.


Aminoglycoside Antibiotics

An interesting area of DMD research has focused on the use of aminoglycoside antibiotics for suppressing stop codons that are responsible for some of the mutations in the dystrophin gene that lead to an absence of dystrophin in muscle cells (1). Preliminary research indicates that gentamicin can suppress stop codons in vitro and in vivo leading to the presence of dystrophin in the cell membrane in skeletal muscles of mdx mice and thus providing some level of protection against injury (1). About 5%–15% of boys with DMD have the disorder because of a premature stop codon in the dystrophin gene. The remaining patients generally have deletions in the dystrophin gene. Considerably more work is required to determine the long-term effects of such treatment. A MDA supported pilot study is currently under way (2001) investigating the use of gentamicin for this group of boys with DMD that have a premature stop codon mutation in the dystrophin gene, and despite the fact that anecdotal reports have appeared regarding this treatment, it is still too early to comment on the relative success of this approach.

There have been several other approaches that have been postulated to be potentially effective for treating muscle wasting with direct relevance to neuromuscular disorders. Unfortunately the scientific validation of many of these approaches is lacking. These include: compounds designed to modulate apoptosis (thought by some to play a role in the progression of muscular dystrophy); growth differentiation factors; tetracycline derivatives; β-endorphin peptides that inhibit enzyme leakage in response to muscle injury; uncoupling proteins (involved in the regulation of energy balance and thermogenesis) for controlling inflammation; and novel tyrosine kinase receptors and ligands used for screening agonists that stimulate muscle growth (10). There have been few studies that support the clinical potential any of these approaches, although some of these treatments, especially growth differentiation factors, are clearly deserving of further investigation (7).


Although considerable effort is currently being directed at developing gene therapies for DMD and related disorders, these techniques are still far from perfect. Alternative therapies for treating neuromuscular disorders are also important, especially efforts directed toward preserving existing muscle tissue, enhancing muscle regeneration, and promoting muscle growth. These treatments can also be adjunctive therapies for increasing the efficacy of genetic- or other cell-based therapies.

Regardless of the approach, there is a profound need for therapeutic intervention strategies that aim to cure or ameliorate the dystrophic condition and improve the quality of life for patients with muscular dystrophy and related neuromuscular disorders. It is important that the efficacy of these therapies be tested rigorously so that real hope can be given to these patients and their families.


The author is grateful for project grant support from the Australian Research Council, the National Health & Medical Research Council of Australia, the Rebecca L. Cooper Medical Research Foundation, and the Muscular Dystrophy Association (U.S.A.).


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muscle wasting; muscular dystrophy; muscle atrophy; cachexia; disuse; force; power

© 2001 Lippincott Williams & Wilkins, Inc.