Muscle Gene Expression Is a Marker of Amyotrophic Lateral Sclerosis Severity

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset degenerative disease characterized by the loss of upper and lower motor neurons leading to progressive muscle atrophy and paralysis. The lack of molecular markers of the progression of disease is detrimental to clinical practice and therapeutic trials. Objective: This study was designed to identify gene expression changes in skeletal muscle that could reliably define the degree of disease severity. Methods: Gene expression profiles were obtained from the deltoid muscles of ALS patients and healthy subjects. Changes in differentially expressed genes were compared to the status of deltoid muscle disability, as determined by manual muscle testing, electrophysiology and the degree of myofiber atrophy. Functionally related genes were grouped by annotation analysis, and deltoid muscle injury was predicted using binary tree classifiers. Results: Two sets of 25 and 70 transcripts appeared differentially regulated exclusively in early and advanced states of deltoid muscle impairment, respectively. The expression of another set of 198 transcripts correlated with a composite score of muscle injury combining manual muscle testing and histological examination. From the totality of these expression changes, 155 transcripts distinguished advanced from early deltoid muscle impairment with 80% sensitivity and 100% specificity. Nine of these transcripts, known also to be regulated in ALS mouse and surgically denervated muscle, predicted the advanced disease status with 100% sensitivity and specificity. Conclusion: We provide robust gene expression changes that can be of practical use when monitoring ALS status and the effects of disease-modifying drugs.

Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression

“…Taken together, patients with ALS exhibited limited increase in muscle HDAC4 messenger RNA levels compared with controls. Our results are consistent with a previous report of HDAC4 induction in muscles of patients with ALS, where fold-change ratios ranged from 1.39 in patients with no muscle function impairment to 2.10 in patients with substantial decrease in muscle function (Pradat et al, 2012). HDAC4 transcript upregulation was significantly greater in patients with rapidly progressive ALS and correlated positively with disease progression rate during follow-up.…”

Creatinine/cystatin C ratio as a surrogate marker of residual muscle mass in amyotrophic lateral sclerosis

“…Furthermore, muscle gene expression changes in skeletal muscle that could reliably define the degree of disease severity were reported. 21 However, we think that the current study presents a more convenient method for assessing disease status and progression than these approaches. Additional methods of measuring limb muscle mass include magnetic resonance imaging (MRI) and bioelectric impedance analysis (BIA).…”

Further development of biomarkers in amyotrophic lateral sclerosis

“…Variations in the expression of genes involved in mitochondrial function and RNA processing have been found in peripheral blood cells of ALS patients [53]. Muscle gene expression has been proposed as a marker of ALS severity [54]. Potentially more sensitive thematic transcriptomic approaches focused on pathophysiological mechanisms can also be used.…”