Fibre Type and Stimulus Determine Progression of Skeletal Muscle Atrophy
Journal Article
Overview
abstract
ABSTRACT; ; Background; Skeletal muscle atrophy is prevalent worldwide and is a major detractor from length and quality of life. It is often diagnosed and treated as a single disorder, but the causal stimuli and progression of atrophy vary widely. Malnutrition and disuse are two common causes of muscle atrophy, and despite their prevalence and extensive characterization, there have been no direct comparisons of how these two types of atrophy progress and whether they differentially affect skeletal muscle fibre types. The purpose of this study is to directly compare atrophy from starvation and disuse and provide a transcriptomic resource for future research.; ; ; Methods; Twelve‐week‐old female C57BL/6 mice were starved for 3 days to induce malnutrition atrophy or were hindlimb suspended (HS) for 3, 7, 14 or 28 days to induce disuse atrophy. At each timepoint, three muscles (tibialis anterior [TA], extensor digitorum longus [EDL] and soleus) were collected, weighed, sectioned and stained, and RNA was extracted for transcriptomic analysis. Atrophy progression and gene expression changes were compared across muscle fibre types and atrophy stimuli.; ; ; Results; We found differences in atrophy progression between muscle fibre types based on fibre twitch speed and atrophy stimulus. Starved mice lost 25% total body weight, 18% fast‐twitch TA mass and 6% TA fibre cross sectional area (CSA), 21% EDL mass and 10% CSA, and 12% soleus mass and 3% CSA. In contrast, 7‐day HS mice lost 18% slow‐twitch soleus, 8% TA mass and 2% EDL mass. The soleus mass loss progressed to ~40% by 14 and 28 days of HS with 20% CSA loss. Gene expression varied across both atrophy stimuli. In starvation, 3618 and 2556 genes were significantly differentially expressed in the EDL and soleus, respectively. With HS, expression of 312 was altered in the EDL and 1072 in the soleus. Gene set enrichment analysis identified increased abundance of aerobic respiration genes in the EDL versus soleus with starvation and increased amino acid metabolism gene expression in the unloaded soleus versus EDL.; ; ; Conclusions; Atrophy progression varies based on stimuli and muscle fibre type. This study provides a large, matched data set where the effects of different atrophic stimuli can be easily and directly compared in multiple fibre types. This work demonstrates that atrophy is not a single disorder at the molecular scale and suggests that therapeutic development may need to be tailored to the atrophic stimulus.;
