Plakoglobin supports length-dependent force generation and cardiac resistance to fasting

Q: What is the clinical evidence from this study?

Population: Fasting-induced skeletal and cardiac muscle atrophy. Intervention: Fasting, AAV9.shJUP plakoglobin knockdown, and U0126 MEK inhibition vs. Fed control, AAV9.shLacz scrambled shRNA, or vehicle-treated fasted mice. Primary outcome: Length-dependent maximal calcium-activated tension (Tmax) at 2.4 μm sarcomere length and muscle mass preservation during fasting.

Q: What does this research mean for the field?

Plakoglobin is required for stretch-induced force generation at long sarcomere lengths in skeletal muscle, while preservation of plakoglobin membrane complexes and MEK-ERK signaling protects cardiac muscle from fasting-induced atrophy. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Samrat Chakraborty; Nashwa Jubran; Stephanie M Deditz; Jonathan A Kirk; Shenhav Shemer

doi:10.64898/2026.10.09.757844

October 13, 2026Open Access

Plakoglobin supports length-dependent force generation and cardiac resistance to fasting

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Key result

Plakoglobin knockdown impairs stretch-induced muscle force, while cardiac muscle preserves plakoglobin and mass during fasting.

Why the study?

Mechanical activity protects muscle from atrophy, and plakoglobin is known to promote insulin-PI3K-AKT-FoxO signaling, yet how contractile forces relate to anabolic signaling remained unclear.

Key Points

To determine how plakoglobin influences stretch-dependent force generation in muscle and whether it mediates the differential susceptibility of skeletal and cardiac muscle to fasting-induced atrophy.
Evaluated subcellular plakoglobin localization in mouse tibialis anterior muscle using super-resolution structured illumination microscopy under fed and two-day fasting conditions.
Knocked down plakoglobin in mice using intravenous AAV9-shJUP and quantified maximal calcium-activated tension and calcium sensitivity in single skinned fibers at sarcomere lengths of 2.1 μm and 2.4 μm.
Assessed membrane-associated protein complexes, insulin-AKT signaling, and atrophy-related gene expression in skeletal and cardiac muscle, including during pharmacological MEK inhibition.
Plakoglobin knockdown did not affect maximal tension at 2.1 μm sarcomere length or calcium sensitivity (EC50), but significantly impaired maximal calcium-activated tension (Tmax) when fibers were stretched to 2.4 μm.
Two days of fasting depleted sarcolemmal plakoglobin complexes, reduced muscle mass, and induced MuRF1 and MAFbx/Atrogin1 in skeletal muscle, whereas cardiac muscle preserved these complexes, active AKT signaling, and mass.
Cardiac tissue resisted AAV-shJUP-mediated plakoglobin depletion, whereas MEK inhibition disrupted this cardioprotection, decreasing AKT signaling, inducing atrogenes, and reducing cardiac mass.

Structured PICO

P

Population

Preclinical mouse model investigating skeletal (tibialis anterior and gastrocnemius) and cardiac muscle responses to 2 days of fasting, AAV9-mediated plakoglobin knockdown, and MEK inhibition.

I

Intervention

48-hour food deprivation (fasting); systemic intravenous tail vein injection (150 μl) of adeno-associated virus serotype 9 encoding shRNA against the mouse plakoglobin gene JUP (AAV9.shJUP, 1×10^12 gc); intraperitoneal injection of MEK inhibitor U0126 at 10 mg/kg body weight administered twice (at the time of food deprivation and 24 hours later)

C

Comparator

Fed control mice; mice receiving AAV9 encoding scrambled shRNA (AAV9.shLacz, 1×10^12 gc via tail vein injection); fasted mice treated with vehicle control (5% DMSO in saline by intraperitoneal injection)

O

Outcome

Muscle mass preservation (cardiac vs. skeletal Tibialis Anterior and Gastrocnemius muscle weights), subcellular distribution of plakoglobin and DGC-insulin receptor signaling complexes, and stretch-induced maximal calcium-activated tension (Tmax) at sarcomere lengths of 2.1 and 2.4 μmsurrogate

This preclinical study demonstrates that plakoglobin supports length-dependent force generation in muscle fibers and that preservation of plakoglobin-containing membrane complexes alongside MEK-ERK signaling mediates cardiac resistance to fasting-induced atrophy.

Limitations

Preclinical animal (mouse) study with no human clinical trial participants.
Because muscle fibers were chemically skinned, the assay does not establish acute mechanical sensing by an intact sarcolemma.
Cardiac plakoglobin resisted AAV9.shJUP-mediated depletion, preventing a direct test of plakoglobin necessity for cardiac protection.
The exact functional relationship between plakoglobin-containing complexes and MEK-ERK signaling in the heart remains to be established.
Because the muscle fibers were chemically skinned, the assay does not establish acute sensing by an intact sarcolemma, and the phenotype may instead reflect persistent effects of plakoglobin loss on membrane-associated cytoskeletal organization and/or on the contractile apparatus.

Implication

Plakoglobin preservation may protect cardiac mass in catabolic states; leaves open MEK-ERK targeting for human skeletal muscle wasting.

Abstract

Mechanical activity protects muscle from atrophy, but how contractile forces relate to anabolic signaling remains unclear. We previously showed that plakoglobin promotes insulin-PI3K-AKT-FoxO signaling and that its loss causes skeletal muscle atrophy. Here, super-resolution microscopy revealed that plakoglobin localizes with desmin at the sarcolemma and is lost from the membrane during fasting-induced skeletal muscle atrophy. In skinned muscle fibers, plakoglobin downregulation impaired stretch-induced increase in myofilament activation at long sarcomere length. During fasting, skeletal muscle lost sarcolemmal plakoglobin-containing complexes, insulin signaling, and mass and induced MuRF1 and MAFbx/Atrogin1. In contrast, cardiac muscle retained these complexes and anabolic signaling, and maintained its mass. Cardiac plakoglobin also resisted AAV-shJUP-mediated depletion despite viral delivery. Moreover, MEK inhibition disrupted this cardiac response, reduced AKT signaling, induced atrogenes, and decreased cardiac mass. Thus, plakoglobin supports force generation at increased sarcomere length, and preservation of plakoglobin-containing complexes and MEK-ERK signaling accompany cardiac resistance to fasting-induced atrophy.

Discussion

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Cite This Study

Chakraborty et al. (2026) studied Fasting-induced skeletal and cardiac muscle atrophy. Fasting, AAV9.shJUP plakoglobin knockdown, and U0126 MEK inhibition vs. Fed control, AAV9.shLacz scrambled shRNA, or vehicle-treated fasted mice was evaluated on Length-dependent maximal calcium-activated tension (Tmax) at 2.4 μm sarcomere length and muscle mass preservation during fasting. Plakoglobin knockdown impaired stretch-induced force generation at 2.4 μm sarcomere length in skeletal muscle, while cardiac muscle preserved plakoglobin complexes and mass during 2-day fasting.

synapsesocial.com/papers/6ae28e56cbadf70daf6c41a5 https://doi.org/10.64898/2026.10.09.757844

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Plakoglobin supports length-dependent force generation and cardiac resistance to fasting

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

Plakoglobin supports length-dependent force generation and cardiac resistance to fasting

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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