Functional classification of skeletal muscle networks. II. Applications to pathophysiology

Abstract

In our preceding companion paper (Wang Y, Winters J, Subramaniam S. J Appl Physiol. doi: 10.1152/japplphysiol.01514.2011), we used extensive expression profile data on normal human subjects, in combination with legacy knowledge to classify skeletal muscle function into four models, namely excitation-activation, mechanical, metabolic, and signaling-production model families. In this paper, we demonstrate how this classification can be applied to study two well-characterized myopathies: amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). Using skeletal muscle profile data from ALS and DMD patients compared with that from normal subjects, normal young in the case of DMD, we delineate molecular mechanisms that are causative and consequential to skeletal muscle dysfunction. In ALS, our analysis establishes the metabolic role and specifically identifies the mechanisms of calcium dysregulation and defects in mitochondrial transport of materials as important for muscle dysfunction. In DMD, we illustrate how impaired mechanical function is strongly coordinated with other three functional networks, resulting in transformation of the skeletal muscle into hybrid forms as a compensatory mechanism. Our functional models also provide, in exquisite detail, the mechanistic role of myriad proteins in these four families in normal and disease function.

Expression of a Mutant SEMA3A Protein with Diminished Signalling Capacity Does Not Alter ALS-Related Motor Decline, or Confer Changes in NMJ Plasticity after BotoxA-Induced Paralysis of Male Gastrocnemic Muscle

“…some male muscles may have relatively more slow, Type I fibers than the same muscle in females, which allows for increased endurance function, thus generating muscles that are capable of sustaining contractile strength. Muscle fibers are also capable of transitioning between subtypes (creating so-called hybrid fibers) in response to injury- or disease-induced changes in synaptic input [59–61] as a compensatory mechanism to maintain muscle function, albeit an altered version of the muscles’ original force and twitch abilities. This mechanism is a dynamic process, and uses a “nearest-neighbor method” to determine which subtype the transitioning fiber will become [60].…”

Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data

“…Two sections per animal were processed using the RNAscope 2.5 Assay as previously described (Wang et al, 2012). Briefly, tissue sections were incubated in a protease treatment for 30 min at RT and then the probes were hybridized to their target mRNAs for 2 hours at 40°C.…”

Cross-laboratory analysis of brain cell type transcriptomes with applications to interpretation of bulk tissue data

“…Fluorescent in situ hybridization probes were designed by Advanced Cell Diagnostics, Inc. (Hayward, CA, USA) to detect mRNA encoding Cox6a2, Slc32a1, and Pvalb. Two sections per animal were processed using the RNAscope® 2.5 Assay as previously described (Wang et al, 2012). Briefly, tissue sections were incubated in a protease treatment for 30 minutes at RT and then the probes were hybridized to their target mRNAs for 2 hours at 40°C.…”