The Role of Calpains in Skeletal Muscle Remodeling with Exercise and Inactivity-induced Atrophy

Abstract

Calpains are cysteine proteases expressed in skeletal muscle fibers and other cells. Although calpain was first reported to act as a kinase activating factor in skeletal muscle, the consensus is now that calpains play a canonical role in protein turnover. However, recent evidence reveals new and exciting roles for calpains in skeletal muscle. This review will discuss the functions of calpains in skeletal muscle remodeling in response to both exercise and inactivity-induced muscle atrophy. Calpains participate in protein turnover and muscle remodeling by selectively cleaving target proteins and creating fragmented proteins that can be further degraded by other proteolytic systems. Nonetheless, an often overlooked function of calpains is that calpain-mediated cleavage of proteins can result in fragmented proteins that are biologically active and have the potential to actively influence cell signaling. In this manner, calpains function beyond their roles in protein turnover and influence downstream signaling effects. This review will highlight both the canonical and noncanonical roles that calpains play in skeletal muscle remodeling including sarcomere transformation, membrane repair, triad junction formation, regulation of excitation-contraction coupling, protein turnover, cell signaling, and mitochondrial function. We conclude with a discussion of key unanswered questions regarding the roles that calpains play in skeletal muscle.

Calpains play an essential role in mechanical ventilation-induced diaphragmatic weakness and mitochondrial dysfunction

“…The function of calpains in skeletal muscle is canonically viewed as supporting myofibrillar protein turnover by releasing sarcomeric proteins for degradation by other proteases (e.g., ubiquitin-proteasome system). In contrast to this view, evidence from previous studies investigating the effect of active calpain on non-muscle cell types suggests that calpains play several roles as signaling effectors in cellular proteolysis [ 29 ]. Indeed, calpains are unique proteases capable of contributing to cell signaling via cleavage of target proteins into biologically active fragments.…”

“…To determine if CAST overexpression successfully prevented the MV-induced activation of calpains in the diaphragm, we measured the abundance of the 145 kDa calpain-specific αII-spectrin cleavage fragment. Specifically, this 145 kDa spectrin cleavage fragment has a relatively long half-life of ~4.2 h and is widely used as a biomarker of calpain activity in vivo [ 23 , [28] , [29] , [30] ]. Our results reveal that overexpression of CAST prevented MV-induced increases in calpain activity in the diaphragm as demonstrated by the significantly higher abundance of the 145 kDa αII-spectrin cleavage product in MV animals compared to all other groups ( Fig.…”

“…Calpains are capable of cleaving substrate proteins into peptide/small protein fragments that have altered biological function relative to the intact protein [ 29 ]. To determine potential mechanisms responsible for the link between MV-induced calpain activity and mitochondrial dysfunction in diaphragm fibers, we measured the abundance of intact and catalyzed protein fragments that are confirmed to promote mitochondrial dysfunction.…”

“…In regard to the calpain isoforms responsible for VIDD, calpain 1, calpain 2, and calpain 3 are the predominant isoforms expressed in skeletal muscle [ 29 ]. However, CAST does not inhibit calpain 3 activity [ 44 ]; therefore, our findings that CAST overexpression protects the diaphragm against VIDD indicate that calpain 1 and/or calpain 2 isoforms are the primary calpain isoforms responsible for the occurrence of VIDD.…”

Disturbances in Calcium Homeostasis Promotes Skeletal Muscle Atrophy: Lessons From Ventilator-Induced Diaphragm Wasting

“…Calpains are a family of Ca 2+ activated proteases that cleave target substrates at specific sites (Goll et al, 2003). Three primary calpain isoforms exist in skeletal muscle (i.e., calpain1, calpain2, and calpain3); although evidence reveals that calpains 1 and 2 play an important role in promoting disuse muscle atrophy, it remains unknown as to whether calpain1 or calpain2 plays the dominant role in promoting fiber atrophy (Hyatt and Powers, 2020).…”