eLifeJul 30, 2026

A muscle protein complex limits muscle length growth when stretched

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 3, 2026

Abstract

Unilateral diaphragm denervation (UDD) in rats and mice leads to upregulation of titin-associated muscle ankyrin repeat proteins (MARPs) and activation of the mTOR pathway.

Titin-based mechanosensing drives signaling related to muscle growth and remodeling.
UDD induces hypertrophy that is dependent on mechanical stretch rather than denervation effects.
Global transcriptomic and proteomic analyses reveal the involvement of MARPs in the hypertrophic response.
Enhanced longitudinal hypertrophy occurs in MARP knockout mice following UDD.
Activation of the mTOR pathway is linked to titin-mediated hypertrophic growth.
Inhibition of mTORC1 with rapamycin suppresses longitudinal hypertrophy, indicating its regulatory role.

Simplified

Titin-based mechanosensing is a key driver of trophic signaling in muscle, yet the downstream pathways linking titin sensing to muscle remodeling remain poorly understood. To investigate these signaling mechanisms, we utilized unilateral diaphragm denervation (UDD), an in vivo model that induces titin-stiffness-dependent hypertrophy via mechanical stretch. Using UDD in rats and mice, we characterized the longitudinal hypertrophic response and distinguished stretch-induced signaling from denervation effects by performing global transcriptomic and proteomic analyses following UDD and bilateral diaphragm denervation (BDD) in rats. Our findings identified upregulation of titin-associated muscle ankyrin repeat proteins (MARPs). Subsequent phosphorylation enrichment mass spectrometry in mouse diaphragm highlighted the involvement of the N2A-element. UDD in MARP knockout (KO) mice resulted in enhanced longitudinal hypertrophy, with Western blot analysis revealing activation of the mTOR pathway. Furthermore, pharmacological inhibition of mTORC1 with rapamycin suppressed longitudinal hypertrophy, demonstrating that mTOR signaling regulates titin-mediated hypertrophic growth in a MARP-dependent manner. These findings establish MARPs as key modulators of titin-based mechanotransduction and highlight mTORC1 as a central regulator of longitudinal muscle hypertrophy.

Full Text

Full text is available at the source.

View Full Text ↗

Funding

Competing interests

No competing interests reported.

PubMed

A muscle protein complex limits muscle length growth when stretched

Abstract

Full Text

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the longevity & aging brief