This is a mechanism module, not a disease; do not create a disuse-atrophy Disease entry from it. Conforming entries substitute their own trigger: disuse or inactivity at the first node; a sensor-gene lesion (FLNC, BAG3, HSPB8, DNAJB6) at the sensor node; ageing at the central effector. Two cautions apply when conforming. (1) The mTORC1-to-protein-synthesis link differs between species. In humans, acute rapamycin blocks the early contraction-induced rise in muscle protein synthesis. In muscle-specific raptor knockout mice, load still raises synthesis although hypertrophy is lost. The edge is kept with both items attached, and the discrepancy is recorded as a human-model-mismatch discussion. (2) The Myofibrillar Myopathy CASA node is primarily a protein-quality-control failure whose terminal lesion is Z-disc aggregation rather than atrophy. It conforms at the sensor node only, because CASA is the tension-induced pathway that senses filamin unfolding; it does not inherit the atrophy chain. Biomechanics (force, strain, tissue-level stress fields) is not represented; the module begins at the cellular sensing of load.
Acute mTORC1 inhibition blocks the load-induced rise in muscle protein synthesis in humans, yet mice with muscle-specific raptor deletion still raise synthesis under load. Is the mouse result a species difference, or an adaptation to chronic loss of mTORC1?
HUMAN MODEL MISMATCH
OPEN
mtorc1_load_induced_synthesis_species_discrepancy
Attached to:
Impaired Load-Dependent mTORC1 Activation
Reduced Myofibrillar Protein Synthesis
The two results differ in species and also in design: an acute drug block in humans against a chronic genetic deletion in mice. If chronic loss of mTORC1 lets another pathway take over synthesis, the human result is the one that applies to acute loading, but it may not apply to the long-term anabolic deficit in sarcopenia or disuse, where the lesion is chronic. This decides whether restoring mTORC1 activity is sufficient to restore synthesis in conforming diseases.
Proposed experiments:
Acute rapamycin versus chronic raptor deletion in loaded mouse muscle
Reduced Mechanical Loading of Skeletal Muscle
trigger
Withdrawal of the contractile and weight-bearing load that skeletal muscle normally experiences: bed rest, limb immobilisation or suspension, reduced step count, spaceflight, or habitual inactivity. In healthy people, absent loading alone is sufficient to cause atrophy.
Downstream
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Z-Disc and Costamere Mechanosensor Dysfunction
Without load there is no input for the mechanosensors to transduce.
Show evidence (1 reference)
"In healthy (i.e., non-disease) states, the absence of muscle loading causes muscle atrophy, as is seen in the case of bed rest"
States that absence of loading is sufficient for atrophy in otherwise healthy humans.
Z-Disc and Costamere Mechanosensor Dysfunction
amplifier
Myofibers sense load through structures that deform under tension. The best characterised is the CASA complex (BAG3 with HSPA8/Hsc70 and HSPB8), which recognises mechanically unfolded filamin C at the Z-disc, routes damaged filamin to autophagy, drives filamin transcription through YAP/TAZ, and positions TSC1/TSC2 to regulate mTORC1. Costamere integrin-FAK signalling and a DGKzeta-phosphatidic acid axis are further candidate sensors. Sensing fails either because there is no load to sense or because a sensor component is lost.
Downstream
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Impaired Load-Dependent mTORC1 Activation
BAG3 binds TSC1 and recruits TSC complexes to the cytoskeleton, relieving mTORC1 inhibition in the rest of the cytoplasm so that strain stimulates translation.
Show evidence (4 references)
"Here, we identify chaperone-assisted selective autophagy (CASA) as a tension-induced autophagy pathway essential for mechanotransduction in muscle and immune cells."
Identifies CASA as a mechanotransduction pathway in muscle.
"The CASA complex, comprised of the molecular chaperones Hsc70 and HspB8 and the cochaperone BAG3, senses the mechanical unfolding of the actin-crosslinking protein filamin."
Names the sensor components and the mechanical event they detect.
"This may e.g. implicate mechanical activation of signaling through a diacylglycerol kinase (DGKζ)-phosphatidic acid (PA) axis or implicate integrin deformation to signal through a Focal adhesion kinase (FAK)-Tuberous Sclerosis Complex 2 (TSC2)-Ras homolog enriched in brain (Rheb) axis."
Names the costamere and phosphatidic-acid candidate sensors.
+ 1 more reference
Impaired Load-Dependent mTORC1 Activation
central effector
The rate-limiting node and key conformance target. Mechanical load activates mTORC1 in the myofiber, and mTORC1 activity is necessary for load-induced hypertrophy and opposes disuse atrophy. When load is absent, the sensor is defective, or the fiber responds weakly (ageing), this activation is lost or blunted. Human rapamycin data tie mTORC1 to the load-induced rise in protein synthesis; a mouse raptor knockout does not (see the module notes and discussion).
Used by disorders
Sarcopenia
as Blunted Load-Induced mTORC1 Signalling
Downstream
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Reduced Myofibrillar Protein Synthesis
The canonical model: mTORC1 drives translation through S6K1 and 4E-BP1, so losing load-dependent activation lowers synthesis. Supported by acute rapamycin in human muscle; contradicted by the chronic raptor knockout in mice.
Show evidence (3 references)
"we were able to directly demonstrate that mechanical stimuli can activate signaling by mTORC1, and that mTORC1 is necessary for mechanical load-induced hypertrophy"
Genetic evidence that load activates mTORC1 and that hypertrophy requires it.
"The Akt/mTOR pathway was upregulated during hypertrophy and downregulated during muscle atrophy."
Pathway activity tracks loading direction in vivo.
"We conclude that aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis."
Human evidence for the blunted-response route by which ageing muscle reaches this node.
Reduced Myofibrillar Protein Synthesis
effector
Without the loading stimulus, myofibrillar protein synthesis falls in both fasted and fed states and responds weakly to feeding. Protein breakdown also falls or stays unchanged in humans, by less, so net balance turns negative.
Downstream
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Skeletal Muscle Fiber Atrophy
A sustained negative protein balance shrinks the fiber.
Show evidence (2 references)
"myofibrillar MPS are reproducibly blunted, resulting in a 30–60% decline in overall MPS"
Quantifies the synthesis decline across human disuse models.
"That said: in humans the most likely scenario is decreases in both MPS and MPB, with the latter being of lesser magnitude"
Supports synthesis rather than breakdown as the dominant driver in human disuse.
Skeletal Muscle Fiber Atrophy
consequence
Loss of fiber cross-sectional area and whole-muscle mass, and with it strength. In conforming diseases this is usually one input to a broader clinical endpoint that also has neural and quality components.
Show evidence (1 reference)
"Finally, genetic activation of the Akt/mTOR pathway was sufficient to cause hypertrophy and prevent atrophy in vivo, whereas genetic blockade of this pathway blocked hypertrophy in vivo."
Shows fiber size follows mTOR pathway activity in vivo, closing the chain to atrophy.
Progressive Resistance Training
Platform:
Behavioral / lifestyle
Restores the missing input. Progressive loading engages the mechanosensors and load-dependent mTORC1 activation. In ageing muscle a higher relative intensity is needed for the same synthetic response.
Evidence: 1
Neuromuscular Electrical Stimulation
Platform:
Device
Evokes contraction without voluntary effort, so it can load muscle during immobilisation, critical illness, or paralysis, when resistance training is impossible.
Evidence: 2