Indirect Evidence for Misfolded Proteins that Accumulate in Muscle to Contribute to the Progression of Sarcopenia
One of the differences between old tissue and young tissue is an accumulation of misfolded proteins, normally soluable, into solid aggregates. The best known of these are the varieties of amyloid that are clearly associated with specific diseases and are present in significant amounts in patient tissues. These are far from the only proteins that accumulate in such a way, however, and there are many more types of misfolded or damaged proteins that do not form aggregates. Unfortunately the mapping of aggregates by tissue to specific consequences in the course of degenerative aging is far from complete. In the paper I'll point out today, the authors take an interesting path in their attempts to prove relevance of various aggregates to age-related loss of muscle mass and strength, the condition known as sarcopenia. I think that the approach is indirect enough to taken as a first filter that leads next to further study to evaluate how well it did, rather than being, on its own, any sort of confirming evidence for the participation of specific aggregates in the progression of sarcopenia. Even that is well before we get into questions of causation versus correlation. The challenge inherent in all investigations of aging is that it is a global phenomenon in the body; there are many correlations to be found between processes that in fact have little to do with one another, and spring from entirely separate sources. Still, the road to knowledge must start somewhere.
Loss of muscle mass and strength is one of the most visible signs of aging, and a large component of the frailty of old age. Once you start to lose strength you start to lose the ability to exercise and the benefits that brings, and things go downhill from there. There are a range of potential approaches to delay this process, of which calorie restriction and exercise are the most accessible and proven, and some near future therapies that could compensate for the loss, adding muscle without addressing the molecular damage of aging that produces sarcopenia as a downstream consequence. In the near future category are myostatin or follistatin gene therapies, and forms of temporary myostatin blockade such as the antibodies currently in clinical trials. Compensation is compensation and better than nothing, but what we really want to see is reversal via therapies that address the root causes of sarcopenia. At the present time there is little evidence as yet to definitively tie sarcopenia to specific root causes of aging, the categories of cell and tissue damage outlined in the SENS rejuvenation research programs. That is in comparison to the many studies linking sarcopenia to age-related changes that are most likely consequences of that damage, such as altered processing of leucine, changes in mitochondrial dynamics, and infiltration of fat into muscle tissue. Given that it is interesting to see people working towards links with protein aggregates, which are very definitely on the SENS list as a target for rejuvenation therapies, even if there is clearly a lot of work left to do to prove this connection via the methodology chosen here.
Age-associated muscle loss, or sarcopenia, results in functional decline that increases the risk for falls, disability, and mortality in older adults. This problem is clearly influenced by factors such as diet, physical activity, genetics, and comorbid health conditions. However, much less is known about the underlying etiology. Aging has detrimental effects on myofibers, satellite cells, and muscle protein synthesis. These effects may be due to dampened levels of growth factors needed for muscle growth and regeneration, or heightened levels of inflammation mediators, which can induce catabolism. Several age-associated diseases, particularly those involving neurodegeneration, feature the accumulation of protein aggregates in affected tissues. Interestingly, similar pathology is also seen for inclusion body myositis, an age-associated degenerative skeletal muscle disease, whose protein aggregates contain the amyloid β peptide characteristic of Alzheimer's disease. In diseased neurons and muscle fibers, aggregation is exacerbated by disruption of proteostasis systems responsible for repair or clearance of misfolded and damaged proteins. Muscle health is expected to be highly reliant on these processes since it reflects a lifetime of continuous mechanical and metabolic stress. However, a causal connection between protein aggregation and muscle aging or sarcopenia has yet to be established.
In the current investigation, we examined protein aggregation that accompanies muscle aging and assessed whether it might contribute to age-associated loss of muscle mass and function. This possibility was suggested by our recent studies which identified and quantified proteins in cardiac muscle aggregates that accrue with aging and hypertension in mice. Our work and that of others has also shown that protein aggregation accumulates with normal aging in the nematode Caenorhabditis elegans and in nematode models of protein-aggregation pathologies. The current study extends our investigation of protein aggregation to human muscle, with three objectives: 1) determine if aging is associated with increased protein aggregation in human skeletal muscle; 2) identify muscle-aggregate proteins that are differentially abundant with age; and 3) identify nematode orthologs of selected human aggregate proteins, and test their mechanistic involvement in protein aggregation and age-associated loss of muscle mass and function in C. elegans.
Previous proteomic comparisons of young and aged muscle for rodents and humans found 3-23% of soluble proteins altered in abundance with age. In the present analysis, 43% of the 515 proteins identified in muscle aggregates differed by at least a 1.5-fold in abundance between age groups, and 15% were significantly different, more than the 5% expected by chance. These results suggest that insoluble protein aggregates may be particularly susceptible to the effects of aging and could play a role in sarcopenia analogous to their role in the pathology of neurodegenerative diseases. This possibility was directly supported by disruptions of gene expression for C. elegans orthologs of human aggregate proteins: six of the seven tested knockdowns reduced protein aggregation and improved muscle-mass retention and resistance to amyloid-induced paralysis in aged nematodes.
By comparing aggregate amounts and compositions across human aging, and assessing functional impacts of aggregate-associated proteins through nematode studies, we were able to demonstrate that age-dependent accumulation of aggregates in muscle can underlie the loss of muscle mass and function that are commonly observed to accompany human aging. Skeletal muscle mass is expected to be influenced by relative rates of protein synthesis and degradation but the current study provides the first evidence that specific proteins are involved in the formation of insoluble protein aggregates that are toxic to muscle. Multiple proteins of diverse function were functionally implicated in protein aggregation, suggesting that the key causal parameter is the aggregate burden itself, rather than an upstream regulator of aggregation. Furthermore, since dampening production of aggregate proteins produced marked improvements in muscle mass and function, we propose that protein aggregation may provide attractive targets for therapeutic intervention in age-dependent sarcopenia. We conclude that protein aggregation is not unique to neurodegenerative disease and genetic myopathies, but is also characteristic of normal muscle aging and may contribute to muscle loss and functional decline with age.