Structural arrangement of the skeletal muscle undergoes remarkable changes in old compared to adult at all levels of organization.

The top panel shows skeletal muscle arrangement in old (right, pink background) versus adult (left, blue background). The middle panels compare the myofiber cross-sections from adult and old muscles. In adult muscle, the SSM and IFM populations are abundant and well-organized, whereas in old muscle their abundance is markedly reduced (especially IFM) and their (ultra)structural features are impaired. The lower panels compare molecular organization of MAM in adult versus old muscle. In adult muscle, MFN1/2, GRP75, VDAC, and IP3R hold the SR and mitochondria in close proximity. Ca2+ released through RyR1 builds up locally termed “Ca2+-microdomain”, which ensure quick mitochondrial Ca2+-influx that activate TCA dehydrogenases thereby enhancing NADH and ATP output and the ETC runs without significant ROS leak. In old muscle, the gap between SR and mitochondria widens as expression of MFN2 and GRP75 decline without a defined Ca2+-microdomain. The MCU uptake slows limiting the mitochondrial Ca2+-influx that reduce ATP production and sustained SERCA activity. In addition RyR1 becomes leaky mainly by ROS-mediated posttranslational modifications leading to increased cytosolic Ca2+ levels. This figure was created using BioRender.com.

Comparison of molecular determinants of mitostasis in skeletal muscle of adult versus old.

Mitostasis is defined by the rates of mitochondrial biogenesis (determined by PGC-1a), dynamics (determined by fusion vs. fission) and mitophagy (determined by PINK/Parkin). In adult muscle (left in blue background), mitochondrial biogenesis is optimal due to ROS from the ETC activates p38, AMPK, and calcineurin, converging on PGC-1a. MFN1/2 and OPA1 sustain favourable mitochondrial network, and PINK/Parkin clears damaged mitochondria before they accumulate maximizing efficient mitochondrial abundance. The proteins responsible for cristae structure maintenance (like MICOS complex) are expressed abundantly that sustain well-organized cristae quantity. Contrastingly, in aging (right in pink background) ROS-level rises to pathological levels, DRP1 activity increases, and the mitochondrial network becomes more fragmented. Expression of MFN1 and MFN2 fall leading to lower fusion rate along with loosening of MAM tethering. MICOS complex gets disorganized leading to deformed cristae and compromised oxidative phosphorylation. Both mitophagy and biogenesis are lessened leading to accumulation of dysfunctional mitochondria. This figure was created using BioRender.com.

Various physiological functions of MAMs under normal conditions.

This schematic presents the typical architecture and function of MAMs in healthy skeletal muscle. The four panels depict mitochondrial Ca2+ influx, SR Ca2+ reuptake, lipid trafficking, and ROS/redox balance that play an integral role in physiological conditions. In the adult muscle, the MAMs integrity ensures efficient mitochondrial Ca2+ influx to facilitate aerobic metabolism and ATP supply. The panel on “SR Ca2+ reuptake” highlights SERCA function in Ca2+ transport back into the SR lumen during normal and cytosolic Ca2+-overload during abnormal conditions. MAMs-mediated lipid trafficking plays a critical role in sustaining relative composition of various lipids and cristae organization supporting mitochondrial dynamics and abundance. ROS generation is maintained at physiological levels, with local antioxidant enzymes (SOD, GPx) preserving redox-sensitive signalling. The structural integrity of the SR membrane and lumen is depicted, highlighting the coordinated regulation of Ca2+, energy, lipid, and redox homeostasis that defines healthy excitation-metabolism coupling. This figure was created using BioRender.com.

Beneficial effects of exercise are routed through MAMs functionality.

Exercise amplifies most of the functionalities of MAMs thereby enhancing the ATP production, Ca2+- crosstalk, lipid trafficking, and ROS handling capacity. Ca2+-microdomain intimacy including greater SR-mediated Ca2+-release and SERCA-based Ca2+-reuptake occur to a greater extent by exercise. Mitochondrial fusion occurs to a higher degree upon adaptation to exercise that require greater influx of lipids to maintain lipid composition. Exercise also is suggested to increase ROS production as well as its scavenging capacity especially near the MAMs. This figure was created using BioRender.com.