Role of Keratin 18 for Stress-induced Adaptive Strength Gains

This project seeks to addresses a critical mechanism underlying sarcopenia and frailty by investigating the role of keratin 18 (Krt18) in skeletal muscle adaptation to repeated eccentric contractions. Sarcopenia, characterized by loss of muscle strength and mass with age, disproportionately contributes to frailty and functional impairment because aged muscle appears less able to adapt to physical stressors. Prior observations indicate that loss of muscle quality, particularly excitation–contraction (EC) coupling failure, is linked to blunted strength adaptations after physical stress or resistance training. Recent data point to Krt18, an intermediate filament protein that associates with the dystrophin-glycoprotein complex, as a potential mediator of stress-induced adaptive strength gains that declines with age. The project is built on compelling preliminary findings: in young mice that experienced strength gains after eccentric exercise, the Krt18 gene was the most highly upregulated (sevenfold), and increased Krt18 protein expression correlated with strength gains and increased expression of membrane-associated proteins. Conversely, old mice exhibited blunted Krt18 expression and markedly lower strength gains compared with young counterparts.

From these observations, the overarching hypothesis is that Krt18 facilitates skeletal muscle adaptation to exercise by increasing plasmalemmal stability and thereby maintaining EC coupling processes that are disrupted by repeated eccentric contractions. If Krt18 supports plasmalemmal integrity and EC coupling, its loss with age may be a key mediator of diminished remodeling capacity and progression toward sarcopenia and frailty. The project comprises two aims designed to test this hypothesis across age groups. Aim 1 will determine whether adaptive strength gains following repeated eccentric contractions are mediated by Krt18 in young mice, using both male and female wildtype and Krt18 knockout animals aged 3–5 months. Aim 2 will determine whether age-related loss of Krt18 expression after repeated eccentric contractions is associated with blunted strength gains, by examining young (3–5 months), adult (20–22 months), and old (27–29 months) male and female wildtype mice. In all groups, mice will undergo repeated bouts of eccentric contractions in vivo while investigators track changes in isometric torque and plasmalemmal excitability. Following the final contractile tests, ex vivo physiology will be employed to indirectly assess EC coupling failure, and markers of muscle damage will be measured.

The study will quantify content of Krt18 and Krt18-interacting proteins such as dystrophin to link molecular changes with functional outcomes. By integrating molecular, physiological, and age-comparative approaches, the project seeks to establish whether the capacity of skeletal muscle to remodel and adapt to repeated physical stress correlates directly with Krt18 expression. Demonstrating that Krt18 promotes plasmalemmal stability and preserves EC coupling would identify a novel mechanism of muscle resiliency and suggest Krt18 as a potential target for interventions to attenuate sarcopenia and frailty. This work, conducted under the auspices of the COM, addresses a fundamental gap in understanding how age-related molecular changes translate into impaired adaptive strength gains and has implications for strategies to preserve muscle function in older adults.