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Given that the consequences of Cr depletion are incompletely understood, we assessed the morphological, metabolic and functional consequences of systemic depletion on skeletal muscle in a mouse model with deficiency of <jats:sc>l<\/jats:sc><jats:italic>\u2010<\/jats:italic>arginine:glycine amidinotransferase (AGAT<jats:sup>\u2212\/\u2212<\/jats:sup>), which catalyses the first step of Cr biosynthesis. <jats:italic>In vivo<\/jats:italic> magnetic resonance spectroscopy showed a near\u2010complete absence of Cr and phosphocreatine in resting hindlimb muscle of AGAT<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Compared with wild\u2010type, the inorganic phosphate\/\u03b2\u2010ATP ratio was increased fourfold, while ATP levels were reduced by nearly half. Activities of proton\u2010pumping respiratory chain enzymes were reduced, whereas F<jats:sub>1<\/jats:sub>F<jats:sub>0<\/jats:sub><jats:italic>\u2010<\/jats:italic>ATPase activity and overall mitochondrial content were increased. The Cr\u2010deficient AGAT<jats:sup>\u2212\/\u2212<\/jats:sup> mice had a reduced grip strength and suffered from severe muscle atrophy. Electron microscopy revealed increased amounts of intramyocellular lipid droplets and crystal formation within mitochondria of AGAT<jats:sup>\u2212\/\u2212<\/jats:sup> muscle fibres. Ischaemia resulted in exacerbation of the decrease of pH and increased glycolytic ATP synthesis. Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT<jats:sup>\u2212\/\u2212<\/jats:sup> mice can be switched between Cr deficient and normal simply by dietary manipulation. Systemic creatine depletion results in mitochondrial dysfunction and intracellular energy deficiency, as well as structural and physiological abnormalities. The consequences of AGAT deficiency are more pronounced than those of muscle\u2010specific creatine kinase deficiency, which suggests a multifaceted involvement of creatine in muscle energy homeostasis in addition to its role in the phosphocreatine\u2013creatine kinase system.<\/jats:p>","DOI":"10.1113\/jphysiol.2012.241760","type":"journal-article","created":{"date-parts":[[2012,11,6]],"date-time":"2012-11-06T05:44:56Z","timestamp":1352180696000},"page":"571-592","source":"Crossref","is-referenced-by-count":91,"title":["Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake"],"prefix":"10.1113","volume":"591","author":[{"given":"C. I.","family":"Nabuurs","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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