Targeting Growth and Atrophy Pathways to Ameliorate Muscle Atrophy and Weakness during Disuse.
Salazar, Jay J.
2009
Abstract
With unloading, muscle atrophy and weakness occur due to changes in both protein synthesis and degradation. The long term goal is to increase understanding of mechanisms underlying the losses in mass and force generation associated with muscle disuse. Our approach was to target both protein degradation, through inhibition of the protease calpain, and growth pathways, through inhibition of deacetylase activity, during hindlimb suspension (HS) to assess the effectiveness for ameliorating structural and functional declines in muscle with unloading. Calpain was inhibited by muscle-specific over-expression of calpastatin in transgenic (cp) mice, and in separate experiments, deacetylase activity was inhibited by treatment with trichostatin A (TSA), previously shown to promote myoblast fusion in culture and induce hypertrophy in dystrophic muscle in vivo. Compared with non-suspended control mice, after 14 days of HS, soleus muscles of wild type (wt) mice showed declines of 25-40% in mass, maximum isometric force (Po), and specific Po normalized for total muscle fiber cross-sectional area (CSA), while muscles of cp mice exhibited similar declines in mass but no change in specific Po. Consistent with preservation of specific Po during HS, muscles of cp mice also maintained sarcomere structure, in contrast to wt muscles that demonstrated misalignment of Z-lines and decreased uniformity of thick filament lengths. We conclude that inhibition of calpain proteolytic activity during unloading preserves sarcomere structure and isometric force generating capacity but does not protect from muscle atrophy. In contrast, treatment with TSA did little to ameliorate the loss of muscle mass during HS and provided no protection from the decrease in specific Po induced by unloading. Although treatment with TSA was ineffective for protecting muscles from atrophy or weakness, individual fiber CSAs were 30-40% larger in TSA treated than in vehicle treated mice after 21 days of HS. These findings indicate that inhibition of deacetylase activity is capable of inducing fiber growth, even in atrophying muscle. In conclusion, calpain inhibition may be an effective target for preventing muscle weakness during disuse, by minimizing proteolytic damage to the force generating apparatus, especially in combination with therapies targeting growth pathways for preventing muscle fiber atrophy.Subjects
TARGETING GROWTH AND ATROPHY PATHWAYS TO AMELIORATE MUSCLE ATROPHY AND WEAKNESS DURING DISUSE AMELIORATION OF MUSCLE ATROPHY AND WEAKNESS BY INHIBITION OF CALPAIN OR DEACETYLASES DURING HINDLIMB SUSPENSION AMELIORATION OF MUSCLE ATROPHY AND WEAKNESS BY INHIBITION OF CALPAIN DURING HINDLIMB SUSPENSION
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