Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder and among the most frequent lethal inherited disease in males, affecting 1 in 3,500 to 5,000 live births. Mutations in the dystrophin gene lead to the loss of functional dystrophin in muscle cells, which destabilizes the dystrophin glycoprotein complex and causes myofiber membrane fragility. DMD is thus characterized by chronic muscle degeneration/regeneration and weakness that progress to wheelchair dependence and premature death. Although pharmacologic corticosteroid therapy mitigates inflammation and slows disease progression, there are currently no curative treatment strategies for DMD.

A hallmark of DMD is the ongoing fusion of muscle stem cells/satellite cells during repeated cycles of muscle regeneration. In a mouse model of DMD (mdx), satellite cell deletion of the fusogenic protein myomaker severely exacerbated existing pathology, whereas myofiber deletion of myomaker improved muscle function and myofiber integrity, indicating a deleterious effect of myofiber expression of myomaker on overall membrane integrity.¹ These findings show that although myocyte fusion is required for effective muscle regeneration in DMD, chronic myomaker activation in dystrophic myofibers due to ongoing fusion contributes to DMD pathology. Single-nucleus transcriptomics in a separate mouse model of DMD lacking dystrophin exon 51 further revealed transcriptional heterogeneity of myonuclei (satellite cell progeny) within normal and dystrophic myofibers and led to the discovery of a distinct regenerative myonuclear population in DMD muscle.² Hence, the collective findings from these recent studies extend critical mechanistic insights into DMD pathogenesis and identify potential molecular targets for novel pharmacologic/genetic therapies.

Gene editing represents the latest advancement in the search for the elusive cure for DMD. In particular, CRISPR/Cas9 editing provides a novel approach to correct DMD by eliminating mutations at the genomic levels and restoring dystrophin expression in myofibers.
Despite initial preclinical successes in DMD, the safety of the CRISPR system needs to be thoroughly validated before clinical translation because of the prevalence of off-target editing and immunogenicity. In addition, the delivery of CRISPR components needs to be further optimized to ensure efficient delivery to skeletal muscles.

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction, caused by antibodies against the acetylcholine receptor (AChR), and it is characterized by skeletal muscle weakness and fatigue. As such, serum testing for autoantibodies to AChR has made diagnosis of myasthenia gravis relatively straightforward in patients with typical symptoms and also identifies the disease subtypes. Detection of anti-AChR antibodies can be performed through several types of assays.³ The most widely used and most specific test is the radioimmunoprecipitation assay (RIPA), which involves the binding of antibodies in the serum to radiolabeled antigens. To avoid radioactivity, an alternative test involves the enzyme-linked immunosorbent assay, although it is considered less specific and sensitive than RIPA. A cell-based assay is another option, although it is difficult to administer in clinical settings and is also less sensitive than RIPA. Besides AChR, autoantibodies to muscle-specific kinase cause a separate myasthenia gravis disease subtype. Muscle-specific kinase autoantibodies and myasthenia gravis account for 6% to 8% of all myasthenia gravis cases and are detected primarily through RIPA.³ In addition to AChR and muscle-specific kinase, recent studies have identified that a small subset of myasthenia gravis is caused by antibodies against low-density lipoprotein receptor-related protein 4.³ Future work will likely continue to elucidate its utility in the clinical diagnosis of myasthenia gravis.

The Myasthenia Gravis Foundation of America assembled a Task Force of international experts in 2013 to develop recommendations for several treatment topics based on the RAND/UCLA appropriateness method. This advisory panel subsequently reconvened in 2019 to update existing recommendations and develop new guidelines for the use of rituximab, eculizumab, and methotrexate as supported by the evidence in a 2021 study.⁴ Rituximab improved clinical outcomes in 68% of patients with AChR-Ab+ myasthenia gravis, with 36% achieving remission.⁵ Eculizumab was effective in reducing myasthenia gravis exacerbation rate by 75% 1 year after treatment, with 56% of patients with refractory generalized AChR-Ab and myasthenia gravis achieving remission.⁶ In addition, functional improvements with eculizumab were maintained through 3 years. With regard to methotrexate, although data supporting its use are limited and unconvincing, the Myasthenia Gravis Foundation of America Task Force recommends its consideration as a corticosteroid-sparing agent in patients with generalized myasthenia gravis in whom other types of steroid-sparing agents are contraindicated.⁴

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder caused by homozygous deletions and point mutations in the survival of motor neuron 1 gene (SMN1). A splicing defect of the neighboring SMN2 gene leads to exon 7 skipping and produces a truncated and unstable protein (SMNΔ7). Clinically, SMA is classified into four subtypes (1 through 4)—in descending order of clinical severity and ascending order of achieved motor function and age of onset. A large-scale correlation analysis has verified that clinical severity in SMA is inversely related to the copy numbers of the SMN2 gene.⁷

To leverage this association to SMA severity, current gene therapies include pharmaceutical agents that alter the splicing of SMN2. The most promising candidate is nusinersen, an antisense oligonucleotide that binds to intron 7 of SMN2 and suppresses the binding of other splice factors. Nusinersen thereby increases exon 7 incorporation into SMN2 messenger RNA transcripts, which promotes the translation of functional full-length SMN proteins. The efficacy of nusinersen in the management of SMA was recently validated in three separate phase III studies (Table 1). In the ENDEAR study, repeated intrathecal injections of nusinersen delayed mortality, reduced the need for ventilator support, and improved motor milestones achievement (Hammersmith Infant Neurological Examination Section 2) in infants (younger than 7 months) with SMA type 1 compared with a sham control group.⁸ In the CHERISH study of children approximately 4 years old with SMA type 2 and onset of symptoms after 6 months of age, nusinersen treatment improved motor functions over baseline levels compared with sham intervention (+4.0 from baseline versus -1.9 from baseline, respectively) based on the Hammersmith Functional Motor Scale Expanded scale.⁹ In infants (younger than 6 weeks) with presymptomatic SMA and carrying two or three copies of the SMN2 gene (NURTURE study), nusinersen facilitated independent sitting and independent walking in 100% and 88% of patients, respectively.¹⁰ Nusinersen has since been approved as the first prescription medicine for SMA by the FDA and the European Medicines Agency and is commercially available as Spinraza.

In addition to altering SMN2 splicing, an alternative gene therapy entails replacement of the SMN1 gene. A single intravenous high dose of onasemnogene abeparvovec (Zolgensma), which carries an adeno-associated viral vector containing DNA that codes for wild-type SMN, improved survival, motor function, and achievement of motor milestones in SMA type 1 infants with 2 SMN2 copies (younger than 8 months) compared with historical cohorts (START study).¹¹ Ongoing work in the STRONG study is currently exploring the effects of onasemnogene abeparvovec (Zolgensma) in children with SMA type 2 (younger than 6 years).

Nemaline myopathies are one of the most common congenital myopathies and are caused by mutations in the genes encoding thin filaments of the sarcomere. As mutations in as many as 12 different genes are associated with nemaline myopathies, they are a genetically and clinically heterogenous group of myopathies. In this regard, nemaline myopathy can be autosomal dominant or recessive and present in different subtypes based on severity. The most severe subtype gives rise to weakness of respiratory muscles, hypotonia, and respiratory failure and eventually leads to early mortality, whereas the milder subtypes are nonprogressive and do not affect life expectancy. To address this heterogeneity and optimize clinical care, a 2021 cross-sectional study attempted to establish the natural history of nemaline myopathy disease.¹² In this study, the most common clinical presentation was typically congenital (54%), which is classified as one of the milder subtypes of nemaline myopathy. Despite this, most of the study cohort required mechanical support (58%), with more than one-fourth of this subgroup (26%) requiring wheelchair, ventilator, and feeding tube assistance.¹² Interestingly, disease progression in patients with unresolved genotypes was worse than in those with identified mutations, indicating that unknown gene mutations regulate the more severe subtypes of nemaline myopathy.

Although there is currently no specific treatment modality for nemaline myopathy, the fast skeletal muscle troponin activator, tirasemtiv, offers a promising pharmacologic therapy for overcoming the associated muscle weakness. Tirasemtiv amplifies the binding between troponin and calcium to expose myosin-binding sites in fast skeletal muscle fibers, thereby enhancing thin filament function and increasing muscle force generation.¹³ In a 2021 study, tirasemtiv successfully improved muscle function and force output in a nemaline myopathy mouse model with an alpha-actin 1 (ACTA1) mutation, a gene commonly modified in patients with nemaline myopathy.¹⁴

A rarer but more deadly muscle disorder is sporadic late-onset nemaline myopathy (SLONM). It is characterized by proximal muscle weakness and atrophy, as well as the presence of nemaline rods in skeletal muscle fibers, and is commonly associated with coexisting conditions such as HIV. A subset of SLONM is associated with the presence of a monoclonal protein, which presents a more aggressive and often lethal disease progression with severe muscle weakness and early respiratory failure.¹⁵ It is currently unclear whether SLONM + monoclonal protein represents a malignant or dysimmune condition. Hence, although chemotherapy has recently been shown to improve survival, neurologic function, and hematologic remission in patients with SLONM + monoclonal protein,¹⁵ there is much debate surrounding whether a chemotherapy-based intervention represents the best treatment modality for this disease. Additional work is needed to further establish the safety and efficacy of this approach.

Idiopathic inflammatory myopathies are a heterogeneous group of rare autoimmune diseases characterized by muscle inflammation (myositis). Apart from muscles, they can manifest in multiple organs and systems,
including the skin, lungs, and joints, often leading to diminished quality of life. Although there is currently no consensus for the classification systems of idiopathic inflammatory myopathies, the five most recognized subtypes of inflammatory myopathies are dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, overlap myositis, and polymyositis.

A 2019 systematic review of physical rehabilitation programs in adult patients with idiopathic inflammatory myopathies concluded physical therapy to be safe during the stable stage of disease and an effective intervention for improving various physiologic and functional outcomes. It consequently recommended rehabilitative programs to include aerobic training three times a week.¹⁶ In 2021, a 24-week supervised training program combining activities of daily living with resistance and stability exercises prevented progressive deterioration and significantly improved muscle strength, endurance, stability, and global disability in patients with idiopathic inflammatory myopathies.¹⁷ These findings emphasize the critical roles of nonpharmacologic interventions, specifically physical exercise and training, in the care and management of adult idiopathic inflammatory myopathies.

The recent coronavirus disease (COVID-19) pandemic has introduced new challenges for patients with idiopathic inflammatory myopathies. Based on case reports, COVID-19 infections exacerbate the disease phenotypes in dermatomyositis and immune-mediated necrotizing myopathy, although the precise pathogenesis of COVID-19-induced myositis is currently unclear. Proposed mechanisms include direct entry of the SARS-CoV-2 virus into muscle tissue via angiotensin-converting enzyme 2 receptors,¹⁸ SARS-CoV-2-induced binding and activation of Toll-like receptor 4 to increase angiotensin-converting enzyme 2 expression, which triggers a hyperinflammatory response in inflamed tissues,¹⁹ or in the case of patients with dermatomyositis, SARS-CoV-2-induced overactivation of CD8 T cells, which triggers the adaptive innate response.²⁰ Furthermore, because of the need for continual follow-up care in patients with idiopathic inflammatory myopathies, limited in-person interaction during the COVID-19 pandemic has led to detrimental effects in one-third of surveyed respondents, with medication-related issues reported as the most common complication.²¹ With a slow recovery in global healthcare underway, remote monitoring and patient self-reported outcomes should be considered to control disease progression in inflammatory myopathies. In particular, self-directed physical assessments such as walking distance test, sit to stand test, and arm raise test are recommended outcome measures for remote monitoring.²²

Volumetric muscle loss is the drastic wasting of skeletal muscle tissue, which arises from surgical ablation and orthopaedic trauma involving extremity injuries. Because of the extensive loss of muscle mass with this pathologic condition, skeletal muscle regenerative capacity is severely compromised, ultimately resulting in significant long-term functional deficits and chronic disability. In response to its increasing prevalence in civilian settings and disproportionate frequencies in military sectors, volumetric muscle loss is an emerging area of study in orthopaedic surgery and regenerative medicine. Despite ongoing efforts, current treatment strategies are limited in restoring muscle mass and function because of incomplete understanding of mechanisms that drive the impaired regenerative response associated with volumetric muscle loss.

The etiology of volumetric muscle loss differs from progressive muscle atrophy associated with aging or disease.²³ Furthermore, endogenous mechanisms of muscle repair/remodeling fail to fully restore function typically observed in other models of acute trauma.²⁴ Specifically, the sustained inability of ablated muscle fibers to regenerate drives functional deficits following volumetric muscle loss.²⁵ This lack of endogenous muscle fiber regeneration can be attributed to the substantial loss of satellite cells and extracellular matrix that formerly reside in the space from which original muscle fibers were ablated. Moreover, volumetric muscle loss alters the immune response through prolonged upregulation of proinflammatory genes, leading to fibrosis throughout the traumatized muscle compartment.²⁶

As surgical intervention and physical therapy fail to improve muscle regeneration, reconstructive therapy such as tissue engineering has emerged as a promising option for building new muscular tissue. Various biologic extracellular matrix and acellular biomaterials have been explored, and occasionally in combination with stem/progenitor cells and assorted growth factors. Recent network meta-analyses determined that the combination of acellular biomaterial with stem/progenitor cells resulted in the greatest improvement in functional deficits.²⁴ Ongoing work in this area is needed to guide the clinical translation of regenerative therapeutics for volumetric muscle loss.

AFM is a polio-like inflammation of the spinal cord that primarily affects children. It is characterized by acute onset of flaccid weakness of one or more limbs,
with lesions targeting the anterior horn cells of the spinal cord and motor nuclei of the brain stem.²⁷ An emerging disorder, AFM is now recognized as a global disease less than a decade since the first reported cases in the United States in 2012. Its clinical presentation mimics other acute neurologic illnesses, and diagnosis is further confounded by the lack of a single specific test for AFM. Despite its infrequency, the acute stage of AFM can result in severe disability with long-term rehabilitation needs. Key insights into this relatively new disease will help guide its assessment, care, and treatment.

AFM in the United States occurs in geographical clusters and follows a seasonal, biennial pattern, as evident by increased cases in 2014, 2016, and 2018. The main driver of these outbreaks is suspected to be enterovirus D68, although the precise mechanism or mechanisms by which this virus strain leads to AFM are currently unknown and need to be fully interrogated. Mild respiratory symptoms and fever are observed in more than 90% of patients with AFM, consistent with the role of enterovirus D68 in respiratory disease. These prodromal illnesses usually precede the onset of neurologic symptoms by 1 to 10 days.²⁸ The presentation of flaccid weakness is typically asymmetric and can manifest in multiple limbs, which subsequently become hyporeflexic or areflexic.²⁷,²⁸ This acute weakness preferentially targets the upper limbs and more profoundly affects proximal muscle groups in the C5 to C6 distribution than distal muscle groups in the C8 to T1 distribution.²⁸ In addition to weakness in the limbs, weakness in the neck, trunk, diaphragm, respiratory muscles, bulbar and facial muscles, and extraocular muscles has also been reported with AFM. The degree of weakness severity is highly variable among patients with AFM, ranging from mild/moderate unilateral limb weakness to complete paralysis of all limbs, and axial and bulbar muscles.²⁷ Assessment of AFM can be complicated by the overlapping of clinical features with other causes of acute flaccid paralysis including Guillain-Barré syndrome, spinal cord stroke, demyelinating myelitis, poliomyelitis, and other infectious myelitides.²⁷ A distinctive clinical feature that distinguishes AFM from these acute neurologic disorders is the aforementioned asymmetry in muscle weakness. This asymmetry can present as severe weakness in upper limbs with normal strength in lower limbs, or a difference of more than 2 points on the Medical Research Council scale between right and left limbs.²⁹

The most useful diagnostic tests for AFM include MRI of the spinal cord and assessment of cerebrospinal fluid pleocytosis levels. In patients with AFM, T2 hyperintensity is prominent in the gray matter of the spinal cord (Figure 1), whereas white blood cell count is slightly elevated during the acute phase (<100/µL) and is restored to normal levels in the subsequent weeks.²⁷,²⁸ In addition to these tests, reverse transcription polymerase chain reaction, although not singularly diagnostic, can further distinguish AFM from other neurologic disorders through viral identification of enterovirus D68. Similarly, although nerve conduction testing does not directly diagnose AFM, the detection of electrophysiologic changes can be valuable in differentiating AFM from other acute neurologic disorders. Because compound motor action potential is reduced or lost several days from the onset of neurologic symptoms, electromyography is particularly useful during the early stages of AFM investigation.²⁷

Recovery from AFM is highly variable and is most rapid in the first few months after onset of symptoms. Although motor strength is improved in most patients during this period, fewer than 10% of patients achieve full recovery from neurologic deficits.²⁷ In particular, limb recovery is weakest in muscle groups scored 0 on the Medical Research Council Scale for Muscle Strength at clinical nadir.²⁹ Early recovery in the limb also appears to occur mainly from a distal to proximal pattern.³⁰ Therefore, limb recovery in patients with AFM can be highly asymmetrical.²⁹

The efficacy of pharmacologic interventions for AFM is impeded by a limited understanding of its pathogenesis, which prevents specific targeting of the underlying molecular mechanism or mechanisms. Current therapeutic strategies include administration of intravenous immunoglobulin, such as neutralizing antibodies, which provides putative antiviral and immunomodulatory effects against the different enterovirus D68 strains.³¹ Other potential therapies for AFM include small-molecule antiviral agents and monoclonal antibodies against nonpolio enteroviruses.³²