Muscle acidosis occurs under ischemic and/or high workload conditions, contributing to hypo-contractility. Striated muscle myosin can use 2-deoxyATP (dATP) during contraction, resulting in greater force at every level of calcium activation when compared to ATP. We previously reported (Robinson-Hamm 2013, Biophys J, 104:484a) that transgenic mice with elevated muscle dATP have increased exercise tolerance and resistance to (in situ) gastrocnemius muscle fatigue. The Debold lab (Longyear 2014, JAPI 116:1165-74) demonstrated that the acidosis-induced depression in thin filament velocity in a motility assay was significantly reduced using dATP vs. ATP with fast skeletal muscle myosin. Thus, we hypothesized that dATP provides a protective effect against reduced contractility in striated muscle. To test this hypothesis, we are measuring the calcium dependence of force in demembranated rat cardiac and soleus muscle, in conjunction with in-vitro motility assays under normal (7.0) and acidic (6.8) conditions. In preliminary studies, decreasing pH from 7.0 to 6.8 in pCa 5.2 activation solution (∼50% of Fmax) reduced steady state specific force of cardiac muscle by 57% when ATP was the myosin substrate for contraction. However, when ATP was replaced with dATP as the contractile substrate, the force decreased by only 25%. These data support our hypothesis that dATP may alleviate the depressive effects of acidosis on myosin crossbridge cycling and muscle contractile capacity. We previously reported that dATP alters myosin structure in a manner that may promote enhanced binding to actin (Nowakowski 2017, Protein Sci 26:749-62), and are currently investigating whether this provides a mechanism for improved resistance to hypo-contraction during muscle acidosis in striated muscle. Supported by R56AG055594 and R01HL128368 to MR and 14GRNT20450002 to ED ∗ Transgenic mouse data reported at 2013 Biophysical Society meeting by Jacqueline Robinson-Hamm. Study with David Marcinek.
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