DIHYDROPYRIDINE RECEPTOR RYANODINE RECEPTOR UNCOUPLING IN AGED SKELETAL-MUSCLE

The mechanisms underlying skeletal muscle functional impairment and st ructural changes with advanced age are only partially understood. In t he present study, we support and expand our theory about alterations i n sarcolemmal excitation-sarcoplasmic reticulum Ca2+ release-contracti on uncoupling as a primary skeletal muscle alteration and major determ inant of weakness and fatigue in mammalian species including humans. T o test the hypothesis that the number of RYR1 (ryanodine receptor) unc oupled to DHPR (dihydropyridine receptor) increases with age, we perfo rmed high-affinity ligand binding studies in soleus, extensor digitoru m longus (EDL) and in a pool of several skeletal muscles consisting of a mixture of fast- and slow-twitch muscle fibers in middle-aged (14-m onth) and old (28-months) Fisher 344 Brown Norway F1 hybrids rats. The number of DHPR, RYR1, the coupling between both receptors expressed a s the DHPR/RYR1 maximum binding capacity, and their dissociation const ant for high-affinity ligands were measured. The DHPR/RYR1 ratio was s ignificantly reduced in the three groups of muscles (pool: 1.03 +/- 0. 15 and 0.80 +/- 0.11, soleus: 0.44 +/- 0.12 and 0.26 +/- 0.10, and EDL : 0.95 +/- 0.14 and 0.68 +/- 0.10, for middle-aged and old muscles, re spectively). These data support the concept that DHPR-RYR1 uncoupling results in alterations in the voltage-gated sarcoplasmic reticulum Ca2 + release mechanism, decreases in myoplasmic Ca2+ elevation in respons e to sarcolemmal depolarization, reduced Ca2+ supply to contractile pr oteins and reduced contraction force with aging.