Role of Keratin 18 for Stress-induced Adaptive Strength Gains

PROJECT SUMMARY
Sarcopenia, loss of muscle strength and mass with age, is a major component of frailty. Muscle weakness
appears to be critical as low strength is associated with more markers of frailty than chronological age. Geriatric
and frail individuals are at greater risk of functional impairments due to an inability of skeletal muscle to adapt to
physical stressors. Strength adaptations in response to physical stress or resistance training have been linked
to loss of muscle quality, particularly excitation contraction (EC) coupling failure. Identifying mechanisms that
counteract contraction-induced EC coupling failure and promote skeletal muscle adaptations are therefore
essential to combating sarcopenia and frailty. Recent data suggest that keratin 18 (Krt18), an intermediate
filament protein that associates with the dystrophin-glycoprotein complex, may be an important mediator of
stress-induced adaptive strength gains that decreases with age. Specifically, we observed that the Krt18 gene
was the most highly upregulated (7-fold) in muscle from young mice that gained strength after eccentric exercise.
We also observed that increased expression of the Krt18 protein and strength gains were associated with
increased expression of membrane-associated proteins. In muscle of old mice, expression of Krt18 was blunted
and strength gains were dramatically lower when compared to young mice. Thus, our overarching hypothesis is
that Krt18 facilitates skeletal muscle adaptation to exercise by increasing plasmalemmal stability to maintain EC
coupling processes that become disrupted by repeated bouts of eccentric contractions. Ultimately, we posit Krt18
may play a role in increasing skeletal muscle resiliency and attenuating development and progression of
sarcopenia and frailty. In Aim 1 we will determine if adaptive strength gains following repeated bouts of eccentric
contractions are mediated by Krt18 in young mice by examining young (3-5-month-old) male and female wildtype
(WT) and Krt18 knockout mice. In Aim 2 we will determine if age-related loss of Krt18 expression in muscle after
repeated bouts of eccentric contractions is associated with blunted strength gains. To integrate age-related
muscle adaptation (or lack thereof) with Krt18 expression, we will use young (3-5 months), adult (20-22 months)
and old (27-29 months) male and female WT mice. All mice will perform repeated bouts of eccentric contractions
in vivo and changes in isometric torque and plasmalemmal excitability will be tracked. Following the last
contractile test, ex vivo physiology will be utilized to indirectly assess EC coupling failure. Markers of muscle
damage will also be assessed and content of Krt18 and Krt18-intereacting proteins (e.g., dystrophin) will be
measured. We predict that the ability of skeletal muscle remodel and adapt to repeated bouts of physical stress
will correlate directly with the level of expression of Krt18, consistent with the idea, that the loss of Krt18 with age
is an important mediator sarcopenia and frailty.

Grant Number: 1R03AG081950-01A1
NIH Institute/Center: NIH
Principal Investigator: Cory Baumann