Muscle wasting in the presence of disease, why is it so variable?
File(s)Kemp Biol Revs accepted.pdf (2.06 MB)
Accepted version
Author(s)
Kemp, P
Griffiths, M
Polkey, M
Type
Journal Article
Abstract
Skeletal muscle wasting is a common clinical feature of many chronic diseases and also occurs in response to single acute events. The accompanying loss of strength can lead to significant disability, increased care needs and have profound negative effects on quality of life. As muscle is the most abundant source of amino acids in the body, it appears to function as a buffer for fuel and substrates that can be used to repair damage elsewhere and to feed the immune system. In essence, the fundamentals of muscle wasting are simple: less muscle is made than is broken down. However, although well‐described mechanisms modulate muscle protein turnover, significant individual differences in the amount of muscle lost in the presence of a given severity of disease complicate the understanding of underlying mechanisms and suggest that individuals have different sensitivities to signals for muscle loss. Furthermore, the rate at which muscle protein is turned over under normal conditions means that clinically significant muscle loss can occur with changes in the rate of protein synthesis and/or breakdown that are too small to be measurable. Consequently, the changes in expression of factors regulating muscle turnover required to cause a decline in muscle mass are small and, except in cases of rapid wasting, there is no consistent pattern of change in the expression of factors that regulate muscle mass. MicroRNAs are fine tuners of cell phenotype and are therefore ideally suited to cause the subtle changes in proteome required to tilt the balance between synthesis and degradation in a way that causes clinically significant wasting. Herein we present a model in which muscle loss as a consequence of disease in non‐muscle tissue is modulated by a set of microRNAs, the muscle expression of which is associated with severity of disease in the non‐muscle tissue. These microRNAs alter fundamental biological processes including the synthesis of ribosomes and mitochondria leading to reduced protein synthesis and increased protein breakdown, thereby freeing amino acids from the muscle. We argue that the variability in muscle loss observed in the human population arises from at least two sources. The first is from pre‐existing or disease‐induced variation in the expression of microRNAs controlling the sensitivity of muscle to the atrophic signal and the second is from the expression of microRNAs from imprinted loci (i.e. only expressed from the maternally or paternally inherited allele) and may control the rate of myonuclear recruitment. In the absence of disease, these factors do not correlate with muscle mass, since there is no challenge to the established balance. However, in the presence of such a challenge, these microRNAs determine the rate of decline for a given disease severity. Together these mechanisms provide novel insight into the loss of muscle mass and its variation in the human population. The involvement of imprinted loci also suggests that genes that regulate early development also contribute to the ability of individuals to resist muscle loss in response to disease.
Date Issued
2019-05-03
Online Publication Date
2019-12-26T07:00:22Z
Date Acceptance
2018-11-27
ISSN
1464-7931
Publisher
Wiley
Start Page
1038
End Page
105
Journal / Book Title
Biological Reviews
Volume
94
Issue
3
Copyright Statement
© 2018 Cambridge Philosophical Society. This is the accepted version of the following article: Kemp, P. R., Griffiths, M. and Polkey, M. I. (2019), Muscle wasting in the presence of disease, why is it so variable?. Biol Rev, 94: 1038-1055, which has been published in final form at https://doi.org/10.1111/brv.12489
Source Database
manual-entry
Sponsor
Royal Brompton & Harefield NHS Foundation Trust
Royal Brompton & Harefield NHS Foundation Trust
Identifier
https://onlinelibrary.wiley.com/doi/full/10.1111/brv.12489
Grant Number
na
BRU6535
Subjects
Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
microRNA
TGF-beta signalling
muscle wasting
susceptibility
protein turnover
OBSTRUCTIVE PULMONARY-DISEASE
HUMAN SKELETAL-MUSCLE
CHRONIC HEART-FAILURE
GROWTH-FACTOR-I
LONG NONCODING RNA
PROTEIN-SYNTHESIS
GENE-EXPRESSION
DIFFERENTIATION FACTOR-15
RESISTANCE EXERCISE
QUADRICEPS MUSCLE
TGF-beta signalling
microRNA
muscle wasting
protein turnover
susceptibility
Evolutionary Biology
06 Biological Sciences
Publication Status
Published
Date Publish Online
2018-12-26