Skeletal muscle fiber force declines with chronic kidney disease in juvenile and adult mice.

Abstract

Juvenile and adult chronic kidney disease (CKD) patients frequently have compromised physical performance, which worsens with disease severity. Examining the underlying mechanisms behind this contractile dysfunction can be difficult to impossible in humans, especially in juveniles, but can be accomplished using animal models. We characterized CKD-induced changes in cellular (single fiber force) and molecular (myosin-actin interactions, myofilament properties) function in soleus and extensor digitorum longus muscles of 6-week-old (juvenile, control = 5, CKD = 6) and 16-week-old (adults, control = 10, CKD = 12) mice. CKD was induced by 0.2% adenine diet for 3 weeks (early-stage CKD) for juveniles and 8 weeks (late-stage CKD) for adults. Maximally activated (pCa 4.5, 25°C) specific tension (maximal isometric force divided by cross-sectional area) was reduced in all myosin heavy chain (MHC) I, IIA, and IIB fibers in juvenile (23-30%) and adult (36-51%) mice with CKD due, in a large part, to a reduction in strongly-bound myosin-actin cross-bridges. Additionally, myofilament stiffness was reduced in MHC IIA fibers from juveniles and adults as well as MHC IIB fibers from adults, potentially reducing force transmission. For adults, myosin-actin interactions were slower in MHC I and IIA fibers. In juveniles, myosin-actin interactions were slower only in MHC IIA fibers but faster in MHC IIB fibers. Fiber cross-sectional area with CKD was increased or unchanged in all fiber types, except for a decrease in MHC IIB fibers from adults. Overall, juvenile early-stage and adult late-stage CKD showed similar molecular mechanisms leading to reduced force production and cross-bridge kinetics, although alterations were generally larger in adult late-stage CKD. Thus, physical function in juvenile early-stage and adult late-stage CKD is being impaired on the molecular level due to intrinsic contractile deficits independent of skeletal muscle atrophy.