Altered energy transfer from mitochondria to sarcoplasmic reticulum after cytoarchitectural perturbations in mice hearts

Abstract

Sarcoplasmic reticulum (SR) calcium pump function requires a high local ATP/ADP ratio, which can be maintained by direct nucleotide channelling from mitochondria, and by SR-bound creatine kinase (CK)-catalysed phosphate-transfer from phosphocreatine. We hypothesized that SR calcium uptake supported by mitochondrial direct nucleotide channelling, but not bound CK, depends on the juxtaposition of these organelles. To test this, we studied a well-described model of cytoarchitectural disorganization, the muscle LIM protein (MLP)-null mouse heart. Subcellular organization was characterized using electron microscopy, and mitochondrial, SR and myofibrillar function were assessed in saponin-permeabilized fibres by measuring respiration rates and caffeine-induced tension transients. MLP-null hearts had fewer, less-tightly packed intermyofibrillar mitochondria, and more subsarcolemmal mitochondria. The apparent mitochondrial K m for ADP was significantly lower in the MLP-null heart than in control (175 ± 15 and 270 ± 33 μM, respectively), indicating greater ADP accessibility, although maximal respiration rate, mitochondrial content and total CK activity were unaltered. Active tension in the myofibres of MLP-null mice was 54% lower than in controls (39 ± 3 and 18 ± 1 mN mm −2 , respectively), consistent with cytoarchitectural disorganization. SR calcium loading in the myofibres of MLP-null mice was similar to that in control myofibres when energy support was provided via Bound CK, but ∼36% lower than controls when energy support was provided by mitochondrial (P < 0.05). Mitochondrial support for SR calcium uptake was also specifically decreased in the desmin-null heart, which is another model of cytoarchitectural perturbation. Thus, despite normal oxidative capacity, direct nucleotide channelling to the SR was impaired in MLP deficiency, concomitant with looser mitochondrial packing and increased nucleotide accessibility to this organelle. Changes in cytoarchitecture may therefore impair subcellular energy transfer and contribute to energetic and contractile dysfunction.

Knockdown of desmin in zebrafish larvae affects interfilament spacing and mechanical properties of skeletal muscle

“…Desmin most likely provides a mechanical link between the terminal Z-disks and the membrane attachment sites (Tidball, 1992), possibly also affecting the localization of other costamere-associated proteins (Carlsson et al, 2000). mitochondrial functions and energy-dependent Ca 2+ handling in cardiac muscle (Wilding et al, 2006). It is possible that alterations in these processes are involved in the lowered active tension of the desmin morphants, although the larval muscles are of a fast phenotype and most likely not critically dependent on aerobic ATP generation during the very short active contractions.…”

Plakins in striated muscle

“…79 In muscle cells, Bpag1/dystonin may interact directly with components of the SR or alternatively may influence the functional properties of the SR by regulating the spacing between the SR and mitochondria. Optimal spacing between the mitochondria and the SR in contractile tissue has been suggested to significantly influence the Ca 2þ uptake potential of the SR by facilitating direct energy (nucleotide) transfer from the mitochondria to the SR. 94 The fact that mitochondrial localization is perturbed in Bpag1/dystonin-deficient skeletal muscles and that these muscles are weaker may suggest that SR function is also disturbed. 22 Although Bpag1/dystonin appears to contribute to ER structure and function, at least in neural cells, it remains to be determined whether this notion also holds true for other cells types, such as muscle (Fig.…”

Cardiomyopathy in α-Kinase 3 (ALPK3)–Deficient Mice

“…Intercalated discs play a central role in establishing the proper alignment of myofibrils and in maintaining the overall structure and mechanical efficiency of cardiomyocytes, and it is known that abnormalities in cardiomyocyte cytoarchitecture can impair efficient energy transfer and contractile force production. 40 The loss of myofibril organization and disruption of intercalated disc structure are common features in many models of cardiomyopathy, and in recent years mutations affecting the structure and composition of the intercalated discs have been recognized in many types of dilated cardiomyopathy. 12,13,31 For example, myofibrillar disarray and intercalated disc abnormalities are hallmark features of cardiomyopathy in muscle LIM protein (MLP)-deficient mice.…”