Scientists identify regenerative checkpoint that limits muscle repair

Good news!

"Researchers ... have identified a molecular mechanism that constrains skeletal muscle regeneration and myofiber repair, a finding that could lead to improved treatment for conditions like muscular dystrophy and severe injury.

To repair muscle, muscle cells, or myocytes, fuse to one another. But the molecular pathways that signal this cell-to-cell fusion have remained poorly defined. ...

The team ... found that platelet-derived growth factor receptor beta (PDGFRb), a receptor protein located in cell membranes, is a key modulator of myocyte function in adult muscle cells. ...

Through in vitro and in vivo experiments, they found that genetic deletion of PDGFRb enhanced muscle regeneration and increased myofiber size, whereas PDGFRb activation impaired muscle repair. ..."

From the abstract:

"Muscle cell fusion is critical for the formation and maintenance of multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood.

Here, we identified platelet-derived growth factor receptor β (PDGFRβ) signaling as a key modulator of myocyte function in adult muscle cells.

Our findings demonstrated that genetic deletion of Pdgfrb enhanced muscle regeneration and increased myofiber size, whereas Pdgfrb activation impaired muscle repair.

Inhibition of PDGFRβ activity promoted myonuclear accretion in both mouse and human myotubes, whereas PDGFRβ activation stalled myotube development by preventing cell spreading to limit fusion potential.

Furthermore, PDGFRβ activity cooperated with TGF-β signaling to regulate myocyte size and fusion. Mechanistically, PDGFRβ signaling required STAT1 activation, and blocking STAT1 phosphorylation enhanced myofiber repair and size during regeneration. Collectively, PDGFRβ signaling acts as a regenerative checkpoint and represents a potential clinical target to improve skeletal muscle repair."

Scientists identify regenerative checkpoint that limits muscle repair | Cornell Chronicle

PDGFRβ signaling restrains myocyte function to limit the regenerative capacity of skeletal muscle (open access)

Fig. 1 PDGFRβ is induced and activated in stimulated muscle progenitor cells.

Mouse study captures and maps aging process of skeletal muscles at the cellular level and in great detail

Good news! It is always good to have a detailed atlas! 

These poor mice were subjected to snake venom.

"As muscles age, their cells lose the ability to regenerate and heal after injury. Cornell Engineering researchers have created the most comprehensive portrait to date of how that change, in mice, unfolds over time and across the complicated architecture of muscle tissue. ...

“Does the decline in regeneration seen in old muscles come from changes to the stem cells that drive the repair process themselves, or does it come from changes in the way that they are instructed by other cell types?” ...

researchers sampled cells from young, old and geriatric mice at six time points after inducing injury via a variant of snake venom toxin. They identified 29 defined cell types, including immune cells that exhibited differences in their abundance and reaction time between age groups, and muscle stem cells that self-renew in youth but stall out as muscles age. ...

The detailed assessment of many cell types over time showed discoordination in the process of muscle repair in older mice. Many immune cells, which coordinate tissue repair, show up at the wrong time. ..."

From the abstract:

"In aging, skeletal muscle regeneration declines due to alterations in both myogenic and non-myogenic cells and their interactions. This regenerative dysfunction is not understood comprehensively or with high spatiotemporal resolution. We collected an integrated atlas of 273,923 single-cell transcriptomes and high-resolution spatial transcriptomic maps from muscles of young, old and geriatric mice (~5, 20 and 26 months old) at multiple time points following myotoxin injury. We identified eight immune cell types that displayed accelerated or delayed dynamics by age. We observed muscle stem cell states and trajectories specific to old and geriatric muscles and evaluated their association with senescence by scoring experimentally derived and curated gene signatures in both single-cell and spatial transcriptomic data. This revealed an elevation of senescent-like muscle stem cell subsets within injury zones uniquely in aged muscles. This Resource provides a holistic portrait of the altered cellular states underlying muscle regenerative decline across mouse lifespan."

Mouse study captures aging process at the cellular level | Cornell Chronicle

Transcriptomic analysis of skeletal muscle regeneration across mouse lifespan identifies altered stem cell states (open access)

Fig. 1: Assembly of scRNA-seq atlas of skeletal muscle regeneration across mouse aging.

Fig. 2: Age-related changes to cell dynamics during skeletal muscle regeneration.

Synced body clocks keep muscles healthy as we age

Amazing stuff! As they say Mens sana in corpore sano!

"As we age, our muscles tend to shrink and get weaker. This loss of mass and strength is a major reason for disability in older people. ... a key player in muscle health: its own internal clock.

... body’s central timekeeper or circadian rhythm, we actually have many internal clocks. Different parts of our bodies have their own timekeepers, and the coordination of these peripheral clocks with the central one in the brain appears to be key to maintaining health. Mice lacking the molecular timekeeping protein Bmal1 in either their brains or their muscles exhibited premature muscle aging, found the new study. Only restoring it in both places allowed the mice’s muscles to stay fit. A study of skin, concurrently published in Cell Stem Cell , came to a similar conclusion. In both studies, the researchers found that the peripheral clock played an important role in interpreting the brain’s timing signals to optimize tissue functioning.

“It is fascinating to see how synchronization between the brain and peripheral circadian clocks plays a critical role in skin and muscle health, while peripheral clocks alone are autonomous in carrying out the most basic tissue functions,” ..."

From the editor's summary and abstract:

"Editor’s summary

Mice lacking the circadian clock component Bmal1 show not only disrupted rhythms but also premature aging and muscle wasting. To explore the specific roles of the central brain clock and the peripheral clock in muscle, Kumar et al. restored clock function by targeted expression of Bmal1 in the brain, skeletal muscle, or both. Restoration of both clocks was needed to substantially inhibit premature aging and muscle dysfunction. The muscle clock alone did not restore rhythmicity but acted to filter signals from the brain clock to achieve proper muscle function. Time-restricted feeding, a behavioral timing cue, could partially substitute for loss of the central clock. Such insights should enhance our understanding of the roles of circadian disruption in aging and provide potential strategies to protect muscle function in aging individuals. ...

Abstract

A molecular clock network is crucial for daily physiology and maintaining organismal health. We examined the interactions and importance of intratissue clock networks in muscle tissue maintenance. In arrhythmic mice showing premature aging, we created a basic clock module involving a central and a peripheral (muscle) clock. Reconstituting the brain-muscle clock network is sufficient to preserve fundamental daily homeostatic functions and prevent premature muscle aging. However, achieving whole muscle physiology requires contributions from other peripheral clocks. Mechanistically, the muscle peripheral clock acts as a gatekeeper, selectively suppressing detrimental signals from the central clock while integrating important muscle homeostatic functions. Our research reveals the interplay between the central and peripheral clocks in daily muscle function and underscores the impact of eating patterns on these interactions."

ScienceAdvisor

Brain-muscle communication prevents muscle aging by maintaining daily physiology (no public access)