In old mice, muscle collects protein clumps, and exercise or rapamycin partly undid the shift

Proteins only work when they are folded into the right shape. Cells spend a lot of effort keeping them that way, and clearing out the ones that misfold, a system biologists call proteostasis (protein balance). With age this system weakens, and misfolded proteins can stick together into clumps. In the brain such clumps are well known from Alzheimer's disease. In muscle, much less is known.

Many attempts to fight age-related muscle loss have tried to make muscle build more protein. A research team that reports this study in a preprint, which is not yet peer-reviewed, argues that the problem may lie more in the quality of the protein that is there. They looked at which proteins in old mouse muscle had become insoluble, meaning they no longer dissolve in a mild detergent and stay behind as solid material.

What they did

The team compared adult mice (4 to 6 months old) with old mice (22 to 24 months), both females and males. Some old mice had a running wheel for up to 60 days; others ate chow containing rapamycin, a drug that blocks the growth signal mTOR and that extends lifespan in mice.

They looked at muscle under light and electron microscopes, using dyes that stain clumped proteins. They then split muscle proteins into a soluble and an insoluble fraction and identified them with proteomics, the large-scale measurement of proteins. Mice were given heavy water, which lets researchers see how fast new protein is made. The protein analyses used 3 to 5 mice per group.

What they found

• Clumps appeared with age. Old muscle held large clumps of the kind cells form to park misfolded proteins, amyloid-like deposits near the cell surface, and what looked like failed waste-disposal compartments (lysosomes that had not finished their job).
• But the total amount of insoluble protein did not rise. Nor did protein building slow down. The bulk of the insoluble material is the muscle's own contractile machinery, which is meant to be solid.
• The change was in the minor proteins. Less common proteins from the mitochondria, the cell nucleus and the scaffolding between cells (collagens and similar) became more likely to end up in the insoluble pile.
• Females changed more. 42 proteins appeared mainly or only in the insoluble fraction of old female muscle, against 11 in old males.
• How "sticky" a protein's sequence is predicted to be did not explain which ones became insoluble.
• Exercise and rapamycin partly reversed the shift. Running lowered the insoluble amount of many proteins, including a collagen that had risen with age. Rapamycin touched fewer proteins but moved more of them back toward the soluble side. Both cut the detection of some proteins that had crept into the insoluble pile with age. Neither increased protein building; rapamycin actually reduced it for the contractile proteins.

What to keep in mind

• This is a mouse study, and a preprint: other scientists have not yet checked it.
• The groups were small (3 to 5 mice per group for the protein analyses), and many results are reported as patterns and "nominally significant" changes for individual proteins.
• The authors say the microscopy was not designed or powered to tell whether females and males differ in the clumps themselves.
• They also note that the functional relevance of the protein changes "remains unknown": the study did not show that the changes make muscles weaker, or that reversing them makes muscles stronger.
• Being insoluble in a lab test is not the same as being harmful; it partly depends on how the proteins are extracted.
• Rapamycin is a prescription drug that suppresses the immune system and has side effects. This study says nothing about its use in people.

Why it matters

The study supports a shift in thinking about aging muscle: from "make more protein" to "keep the protein you have in good shape". The finding that exercise changed the insoluble proteins without boosting protein building fits that view. Whether the same changes happen in human muscle, and whether they matter for strength, are questions for further work.