Clinical and imaging hallmarks of the MYH7‐related myopathy with severe axial involvement

Introduction: MYH7 gene mutations are related to a heterogeneous group of skeletal and cardiac myopathies. Methods: We evaluated clinical and muscle MRI changes in patients with mutations in the rod domain of MYH7, including 1 with mosaicism and 3 with novel missense mutations. Results: Patients presented in childhood with a distal and axial phenotype. Biopsy findings were variable. Half of the cases displaying some type of core pathology, including minicores and eccentric cores. Most patients demonstrated internal bands of infiltration (“inverted‐collagen‐VI sign”) in multiple muscles, particularly the soleus, and prominent atrophy and fatty infiltration of the tongue and the paraspinal, gluteus minimus, sartorius, gracilis, tibialis anterior, and extensor digitorum longus muscles. Discussion: Muscle imaging findings in patients with axial involvement provide significant clues permitting the distinction between MYH7‐related myopathies and other axial myopathies such as those related to SEPN1 and LMNA genes. Muscle Nerve 58 : 224–234, 2018     

Muscle magnetic resonance imaging and histopathology in ACTA1‐related congenital nemaline myopathy

Introduction: Muscle biopsy is usually diagnostic in nemaline myopathy (NM), but some patients may show nonspecific findings, leading to pitfalls in diagnosis. Muscle MRI is a helpful complementary tool. Methods: We assessed the clinical, histopathological, MRI, and molecular findings in a 19‐year‐old patient with NM in whom 2 muscle biopsies with ultrastructural examination showed no nemaline bodies. We analyzed the degree and pattern of muscle MRI involvement of the entire body, including the tongue and pectoral muscles. Results: Muscle MRI abnormalities in sartorius, adductor magnus, and anterior compartment muscles of the leg suggested NM. A previously unreported fatty infiltration of the tongue was found. A third biopsy after the muscle MRI showed scant nemaline bodies. A novel heterozygous de novo ACTA1 c.611C>T/p.Thr204Ile mutation was detected. Conclusions: We highlight the contribution of muscle imaging in addressing the genetic diagnosis of ACTA1‐related NM. Muscle Nerve 50: 1011–1016, 2014     

Three‐tesla magnetic resonance neurography of the brachial plexus in cervical radiculopathy

Introduction: There have been no reports of the use of 3‐Tesla magnetic resonance neurography (3T MRN) to characterize cervical radiculopathy. In particular, there are no reports of MRN of brachial plexus involvement in patients with cervical radiculopathy. Methods: We reviewed retrospectively 12 consecutive patients with cervical radiculopathy who underwent 3T MRN. Results: The median age was 54.5 years. Eleven of 12 patients were men. The distribution of nerve‐root signal abnormality was correlated with intervertebral foraminal stenosis and the presence of muscles that exhibited weakness and/or signs of denervation on electromyography. MRN abnormalities were found to extend into the distal part of the brachial plexus in 10 patients. Conclusion: This study demonstrates that MRN is potentially useful for diagnosis in patients with suspected cervical radiculopathy. Moreover, the finding of brachial plexus involvement on MRN may indicate a possible pathophysiological relationship between cervical radiculopathy and brachial plexopathy. Muscle Nerve 52:392–396, 2015     

Pattern of skeletal muscle involvement in primary dysferlinopathies: a whole‐body 3.0‐T magnetic resonance imaging study

Objectives and methods – Mutations in the gene encoding dysferlin cause limb girdle muscular dystrophy type 2B (LGMD2B), distal Miyoshi myopathy (MM), and a rare form of distal anterior compartment myopathy. To study the correlations between clinical manifestations and muscle imaging changes we conducted a 3.0‐T magnetic resonance imaging (MRI) study in six German patients with primary dysferlinopathies defined by absence of dysferlin expression in muscle (MM, n = 3; LGMD2B, n = 2; hyperCKemia without clinical symptoms, n = 1). Results – Patients with manifest myopathy had widespread muscular pathology. In analogy to previous imaging studies, we confirmed an involvement of the anterior and posterior thigh compartments and a predominant involvement of posterior lower legs. However, our whole‐body MRI study further provided evidence of signal alterations in the glutei, erector spinae and shoulder girdle muscles. Correlation of clinical findings with imaging demonstrated the potential of MRI to detect subclinical muscle pathology. Conclusions – Whole‐body 3.0‐T MRI is a non‐invasive method to demonstrate various degrees of skeletal muscle alterations and disease progression in muscular dystrophies. Furthermore, whole‐body high‐field MRI may serve as a helpful diagnostic tool in differentiating primary dysferlinopathies from other forms of LGMD and distal myopathies.     

Vastus lateralis exhibits non‐homogenous adaptation to resistance training

Introduction: Variations in transverse point of measure on the vastus lateralis (VL) may significantly affect the relationship between structure and function. The purpose of this study was to compare changes in muscle architecture at 2 commonly used points of measure (VL0 and VL5). Methods: Maximal strength (1‐repetition maximum [1RM] barbell squat) and muscle architecture were assessed PRE and POST 15 weeks of periodized resistance training. VL0 was 50% of the straight line distance between the greater trochanter and lateral epicondyle of the femur. VL5 was 5cm medial to VL0. Results: Increases in 1RM strength (3.7 ± 2.4 kg; P = 0.004) were observed. Changes in muscle thickness (MT) at VL5 were significantly greater than at VL0 (P = 0.006). Changes in strength correlated with changes in muscle architecture at VL0 only (MT: r = 0.561; fascicle length: r = 0.503). Conclusions: Changes in muscle architecture appear to occur in a non‐homogeneous manner. Muscle Nerve 50 : 785–793, 2014     

Repetitive stretch suppresses denervation‐induced atrophy of soleus muscle in rats

This study was conducted to examine whether stretch‐related mechanical loading on skeletal muscle can suppress denervation‐induced muscle atrophy, and if so, to depict the underlying molecular mechanism. Denervated rat soleus muscle was repetitively stretched (every 5 s for 15 min/day) for 2 weeks. Histochemical analysis showed that the cross‐sectional area of denervated soleus muscle fibers with repetitive stretching was significantly larger than that of control denervated muscle (P < 0.05). We then examined the involvement of the Akt/mammalian target of the rapamycin (mTOR) cascade in the suppressive effects of repetitive stretching on muscle atrophy. Repetitive stretching significantly increased the Akt, p70S6K, and 4E‐BP1 phosphorylation in denervated soleus muscle compared to controls (P < 0.05). Furthermore, repetitive stretching‐induced suppression of muscle atrophy was fully inhibited by rapamycin, a potent inhibitor of mTOR. These results indicate that denervation‐induced muscle atrophy is significantly suppressed by stretch‐related mechanical loading of the muscle through upregulation of the Akt/mTOR signal pathway. Muscle Nerve, 2009     

Whole‐body high‐field MRI shows no skeletal muscle degeneration in young patients with recessive myotonia congenita

Kornblum C, Lutterbey GG, Czermin B, Reimann J, von Kleist‐Retzow J‐C, Jurkat‐Rott K, Wattjes MP. Whole‐body high‐field MRI shows no skeletal muscle degeneration in young patients with recessive myotonia congenita.
Acta Neurol Scand: 2010: 121: 131–135.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background – Muscle magnetic resonance imaging (MRI) is the most sensitive method in the detection of dystrophic and non‐dystrophic abnormalities within striated muscles. We hypothesized that in severe myotonia congenita type Becker muscle stiffness, prolonged transient weakness and muscle hypertrophy might finally result in morphologic skeletal muscle alterations reflected by MRI signal changes. Aim of the study – To assess dystrophic and/or non‐dystrophic alterations such as fatty or connective tissue replacement and muscle edema in patients with severe recessive myotonia congenita. Methods – We studied three seriously affected patients with myotonia congenita type Becker using multisequence whole‐body high‐field MRI. All patients had molecular genetic testing of the muscle chloride channel gene (CLCN1). Results – Molecular genetic analyses demonstrated recessive CLCN1 mutations in all patients. Two related patients were compound heterozygous for two novel CLCN1 mutations, Q160H and L657P. None of the patients showed skeletal muscle signal changes indicative of fatty muscle degeneration or edema. Two patients showed muscle bulk hypertrophy of thighs and calves in line with the clinical appearance. Conclusions – We conclude that (i) chloride channel dysfunction alone does not result in skeletal muscle morphologic changes even in advanced stages of myotonia congenita, and (ii) MRI skeletal muscle alterations in myotonic dystrophy must be clear consequences of the dystrophic disease process.     

Age‐related effect of cell death on fiber morphology and number in tongue muscle

Introduction: Multiple pathways may exist for age‐related tongue muscle degeneration. Cell death is one mechanism contributing to muscle atrophy and decreased function. We hypothesized with aging, apoptosis, and apoptotic regulators would be increased, and muscle fiber size and number would be reduced in extrinsic tongue muscles. Methods: Cell death indices, expression of caspase‐3 and Bcl‐2, and measures of muscle morphology and number were determined in extrinsic tongue muscles of young and old rats. Results: Significant increases in cell death, caspase‐3, and Bcl‐2 were observed in all extrinsic tongue muscles along with reductions in muscle fiber number in old rats. Discussion: We demonstrated that apoptosis indices increase with age in lingual muscles and that alterations in apoptotic regulators may be associated with age‐related degeneration in muscle fiber size and number. These observed apoptotic processes may be detrimental to muscle function, and may contribute to degradation of cranial functions with age. Muscle Nerve 57 : E29–E37, 2018     

Spinal charcot‐marie‐tooth disease: A reappraisal

Introduction: Distal hereditary motor neuropathy (dHMN) is characterized by isolated distal muscle atrophy without sensory deficit. Nevertheless, clinical sensory loss has been reported despite preserved sensory nerve conduction in a few patients, thus differentiating these cases from the classical type 2 Charcot‐Marie‐Tooth disease (CMT2). Methods: We report 4 patients who presented with clinical sensory and motor neuropathy and normal peripheral sensory nerve conduction studies and were investigated with complete electrophysiological studies, including somatosensory evoked potentials (SEP). Results: These patients had a clinical presentation of classical CMT with isolated axonal motor neuropathy suggestive of dHMN. Interestingly, tibial nerve SEPs showed abnormalities suggestive of proximal involvement of dorsal roots that may explain the clinical somatosensory disturbances. Conclusions: These cases support the concept of spinal CMT that should be recognized as an intermediate form between dHMN and CMT2. SEP recording was helpful in defining a more precise phenotype of spinal CMT. Muscle Nerve 46: 603–607, 2012     

Late‐onset Becker muscular dystrophy: Refining the clinical features and electrophysiological findings

Introduction: The aim of this study was to characterize a unique distribution of muscle involvement in sporadic Becker muscle dystrophy (BMD). Methods: Retrospective chart review, clinical examination, electrophysiological studies, cardiac testing, and genetic testing were performed in 5 patients. Results: Predominant weakness and atrophy of biceps brachii, hip adduction, and quadriceps muscles was noted along with calf and extensor forearm hypertrophy. Finger flexor muscles were severely weak in 3 of 5 patients, a feature that could lead to a misdiagnosis of inclusion body myositis. Creatinine kinase was only mildly elevated in most patients. Electromyography was abnormal in all patients. Muscle biopsy in 1 patient demonstrated normal immunostaining for dystrophin. Conclusions: We found a unique and uniform distribution of muscle involvement in 5 sporadic cases of BMD. Recognizing these features is important for differentiating it from other myopathies that may have similar features and avoids unnecessary invasive procedures such as muscle biopsy. Muscle Nerve 52 : 885–887, 2015     

Effect of dys‐1 mutation on gene expression profile in space‐flown Caenorhabditis elegans

Introduction: Dystrophin‐like dys‐1 gene expression increases in the body wall muscles of Caenorhabditis elegans after spaceflight (SF). Here we used a dys‐1(cx18) mutant to analyze the molecular adaptive responses of C. elegans to SF. Methods: DNA microarrays were performed to identify differentially expressed genes between wild‐type (WT) and dys‐1 mutant worms after SF. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, predicted human diseases, and screened out key genes for human muscle diseases with NextBio. Results: Gene expression was less affected by SF in the dys‐1 mutant than in the WT worms. The dys‐1 mutation influenced neuromuscular gene expression (neuropeptide genes, muscle‐related genes, and dystrophin‐related genes) under SF conditions, among which 15 genes were specifically regulated by dys‐1. NextBio analysis predicted that cdka‐1, lev‐11, unc‐27, and unc‐94 genes might play critical roles in muscle atrophy. Discussion: dys‐1 Potentially regulates the neuromuscular system in space. Muscle Nerve 58 : 114–122, 2018     

Rigid spine syndrome associated with sensory‐motor axonal neuropathy resembling Charcot–Marie‐Tooth disease is characteristic of Bcl‐2‐associated athanogene‐3 gene mutations even without cardiac involvement

Introduction: Bcl‐2‐associated athanogene‐3 (BAG3) mutations have been described in rare cases of rapidly progressive myofibrillar myopathies. Symptoms begin in the first decade with axial involvement and contractures and are associated with cardiac and respiratory impairment in the second decade. Axonal neuropathy has been documented but usually not as a key clinical feature. Methods: We report a 24‐year‐old woman with severe rigid spine syndrome and sensory‐motor neuropathy resembling Charcot–Marie–Tooth disease (CMT). Results: Muscle MRI showed severe fat infiltration without any specific pattern. Deltoid muscle biopsy showed neurogenic changes and discrete myofibrillar abnormalities. Electrocardiogram and transthoracic echocardiography results were normal. Genetic analysis of a panel of 45 CMT genes showed no mutation. BAG3 gene screening identified the previously reported c.626C>T, pPro209Leu, mutation. Discussion: This case indicates that rigid spine syndrome and sensory‐motor axonal neuropathy are key clinical features of BAG3 mutations that should be considered even without cardiac involvement. Muscle Nerve, 57 : 330–334, 2018     

Neuromuscular choristoma presenting with unilateral limb hypoplasia in a 3‐year‐old boy

Introduction: Neuromuscular choristomas (NMCs) are rare benign peripheral nerve lesions in which skeletal muscle tissue is admixed with nerve fascicles. Methods: We describe a case of sciatic nerve NMC presenting with unilateral limb hypoplasia, monoparesis, and equinovarus contracture in a pediatric patient. We outline the unique clinical presentation and diagnostic work‐up for our patient, including electromyographic and imaging studies. Results: MRI revealed fusiform enlargement of the sciatic nerve, <50% intralesional fat, and signal characteristics similar to those of muscle tissue. Ultrasound was utilized to characterize atrophy and fatty infiltration of affected muscles. The patient was treated conservatively with a customized physical therapy program and lower limb orthosis. Conclusions: Emerging diagnostic criteria are highlighted with the goal of distinguishing NMCs from more common peripheral nerve lesions. This can have important clinical consequences, as unnecessary biopsies are associated with aggressive fibromatosis, a potentially devastating complication. Muscle Nerve 54 : 797–801, 2016     

Inflammatory response during slow‐ and fast‐twitch muscle regeneration

Introduction: Skeletal muscles are characterized by their unique ability to regenerate. Injury of a so‐called fast‐twitch muscle, extensor digitorum longus (EDL), results in efficient regeneration and reconstruction of the functional tissue. In contrast, slow‐twitch muscle (soleus) fails to properly reconstruct and develops fibrosis. This study focuses on soleus and EDL muscle regeneration and associated inflammation. Methods: We determined differences in the activity of neutrophils and M1 and M2 macrophages using flow cytometry and differences in the levels of proinflammatory cytokines using Western blotting and immunolocalization at different times after muscle injury. Results: Soleus muscle repair is accompanied by increased and prolonged inflammation, as compared to EDL. The proinflammatory cytokine profile is different in the soleus and ED muscles. Conclusions: Muscle repair efficiency differs by muscle fiber type. The inflammatory response affects the repair efficiency of slow‐ and fast‐twitch muscles. Muscle Nerve 55 : 400–409, 2017     

Apigenin inhibits sciatic nerve denervation–induced muscle atrophy

Introduction: Apigenin (AP) has been reported to elicit anti‐inflammatory effects. In this study, we investigated the effect of AP on sciatic nerve denervation–induced muscle atrophy. Methods: Sciatic nerve–denervated mice were fed a 0.1% AP‐containing diet for 2 weeks. Muscle weight and cross‐sectional area (CSA), and the expression of atrophic genes and inflammatory cytokines in the gastrocnemius were analyzed. Results: Denervation significantly induced muscle atrophy. However, values for muscle weight and CSA were greater in the denervated muscle of the AP mice than the controls. AP suppressed the expression of MuRF1, but upregulated both myosin heavy chain (MHC) and MHC type IIb. AP also significantly suppressed expression of tumor necrosis‐alpha in the gastrocnemius and soleus muscles, and interleukin‐6 expression in the soleus muscle. Discussion: AP appears to inhibit denervation‐induced muscle atrophy, which may be due in part to its inhibitory effect on inflammatory processes within muscle. Muscle Nerve 58 : 314–318, 2018     

Training at non‐damaging intensities facilitates recovery from muscle atrophy

Introduction: Resistance training promotes recovery from muscle atrophy, but optimum training programs have not been established. We aimed to determine the optimum training intensity for muscle atrophy. Methods: Mice recovering from atrophied muscles after 2 weeks of tail suspension underwent repeated isometric training with varying joint torques 50 times per day. Results: Muscle recovery assessed by maximal isometric contraction and myofiber cross‐sectional areas (CSAs) were facilitated at 40% and 60% maximum contraction strength (MC), but at not at 10% and 90% MC. At 60% and 90% MC, damaged and contained smaller diameter fibers were observed. Activation of myogenic satellite cells and a marked increase in myonuclei were observed at 40%, 60%, and 90% MC. Conclusions: The increases in myofiber CSAs were likely caused by increased myonuclei formed through fusion of resistance‐induced myofibers with myogenic satellite cells. These data indicate that resistance training without muscle damage facilitates efficient recovery from atrophy. Muscle Nerve 55 : 243–253, 2017     

Quantitative muscle ultrasound and quadriceps strength in patients with post‐polio syndrome

Introduction: We investigated whether muscle ultrasound can distinguish muscles affected by post‐polio syndrome (PPS) from healthy muscles and whether severity of ultrasound abnormalities is associated with muscle strength. Methods: Echo intensity, muscle thickness, and isometric strength of the quadriceps muscles were measured in 48 patients with PPS and 12 healthy controls. Results: Patients with PPS had significantly higher echo intensity and lower muscle thickness than healthy controls. In patients, both echo intensity and muscle thickness were associated independently with muscle strength. A combined measure of echo intensity and muscle thickness was more strongly related to muscle strength than either parameter alone. Conclusions: Quantitative ultrasound distinguishes healthy muscles from those affected by PPS, and measures of muscle quality and quantity are associated with muscle strength. Hence, ultrasound could be a useful tool for assessing disease severity and monitoring changes resulting from disease progression or clinical intervention in patients with PPS. Muscle Nerve 51 : 24–29, 2015     

Load‐controlled moderate and high‐intensity resistance training programs provoke similar strength gains in young women

Introduction: While current exercise guidelines recommend progressive, high‐intensity resistance training (RT) to promote muscle hypertrophy and strength gains, controversy exists regarding the efficacy of lighter‐load RT. We compared 2 work‐matched RT interventions that differed in training intensity. Methods: Fifteen women underwent 10 weeks of unilateral knee extensor RT. One leg was trained at increasing intensity (intensity leg, InL, 50–80% 1‐repetition maximum [1‐RM]), and training progression in the contralateral leg (volume leg, VoL, 50% 1‐RM) was based on increasing training volumes. Quadriceps muscle size (ultrasound, dual energy X‐ray absorptiometry) and strength (isokinetic dynamometry) were assessed on 4 occasions. Results: Both training programs induced significant, yet comparable increases in muscle size (InL: +4.6–12%, VoL: +3.1–11%) and strength (InL: +10–16%, VoL: +10–14%). Conclusions: Training at lower than commonly suggested intensities may be an equally effective alternative form of RT. Factors other than training intensity, such as the total mechanical work during training, may strongly affect the training response. Muscle Nerve 51 : 92–101, 2015     

Longitudinal 2‐point dixon muscle magnetic resonance imaging in becker muscular dystrophy

Introduction: Quantitative MRI techniques detect disease progression in myopathies more sensitively than muscle function measures or conventional MRI. To date, only conventional MRI data using visual rating scales are available for measurement of disease progression in Becker muscular dystrophy (BMD). Methods: In 3 patients with BMD (mean age 36.8 years), the mean fat fraction (MFF) of the thigh muscles was assessed by MRI at baseline and at 1‐year follow‐up using a 2‐point Dixon approach (2PD). The motor function measurement scale (MFM) was used for clinical assessment. Results: The mean MFF of all muscles at baseline was 61.6% (SD 7.6). It increased by 3.7% to 65.3% (SD 4.7) at follow‐up. The severity of muscle involvement varied between various muscle groups. Conclusions: As in other myopathies, 2PD can quantify fatty muscle degeneration in BMD and can detect disease progression in a small sample size and at relatively short imaging intervals. Muscle Nerve 51 : 918–921, 2015     

Bioenergetics and intermuscular fat in chronic obstructive pulmonary disease‐associated quadriceps weakness

Introduction: Chronic obstructive pulmonary disease (COPD) is associated with metabolic abnormalities in muscles of the lower limbs, but it is not known whether these abnormalities are generalized or limited to specific muscle groups, nor is there an easy way of predicting their presence. Methods: Metabolism in the quadriceps and biceps of 14 COPD patients and controls was assessed during sustained contraction using 31‐phosphorus magnetic resonance spectroscopy (³¹P MRS). T1 MRI was used to measure quadriceps intermuscular adipose tissue (IMAT). Results: COPD patients had prolonged quadriceps phosphocreatine time (patients: 38.8 ± 12.7 s; controls: 25.2 ± 10.6 s; P = 0.006) and a lower pH (patents: 6.88 ± 0.1; controls: 6.99 ± 0.06; P = 0.002). Biceps measures were not significantly different. IMAT was associated with a nadir pH <7.0 (area under the curve = 0.84). Conclusions: Anaerobic metabolism during contraction was characteristic of quadriceps, but not biceps, muscles of patients with COPD and was associated with increased IMAT. Because IMAT can be assessed quickly by conventional MRI, it may be a useful approach for identifying patients with abnormal muscle bioenergetics. Muscle Nerve 51 : 214–221, 2015